The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index; none of the 52 sources its claims cite is checked for support yet.
Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study.
Open accessAbstract
Flavone and isoflavone phytoestrogens are plant chemicals and are known to be competitive inhibitors of cytochrome P450 aromatase with respect to the androgen substrate. Aromatase is the enzyme that converts androgen to estrogen; therefore, these plant chemicals are thought to be capable of modifying the estrogen level in women. In this study, the inhibition profiles of four flavones [chrysin (5, 7-dihydroxyflavone), 7,8-dihydroxyflavone, baicalein (5,6,7-trihydroxyflavone), and galangin (3,5,7-trihydroxyflavone)], two isoflavones [genistein (4,5,7-trihydroxyisoflavone) and biochanin A (5,7-dihydroxy-4-methoxyisoflavone)], one flavanone [naringenin (4, 5,7-trihydroxyflavanone)], and one naphthoflavone (alpha-naphthoflavone) on the wild-type and six human aromatase mutants (I133Y, P308F, D309A, T310S, I395F, and I474Y) were determined. In combination with computer modeling, the binding characteristics and the structure requirement for flavone and isoflavone phytoestrogens to inhibit human aromatase were obtained. These compounds were found to bind to the active site of aromatase in an orientation in which rings A and C mimic rings D and C of the androgen substrate, respectively. This study also provides a molecular basis as to why isoflavones are significantly poorer inhibitors of aromatase than flavones.
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TL;DR
This study combined inhibition kinetics, site-directed aromatase mutants, and computer modeling to examine how flavone and isoflavone phytoestrogens bind and inhibit human aromatase. It found that flavones generally inhibit more strongly than isoflavones, with α-naphthoflavone and chrysin most potent, and proposed a binding orientation in which the flavone A and C rings mimic the steroid D and C rings while the C4-keto group faces the heme.
Key findings
- Among the tested compounds, α-naphthoflavone had the lowest Ki (2.2 ± 0.1 µM), followed by chrysin (2.6 ± 0.1 µM), naringenin (5.1 ± 0.2 µM), 7,8-dihydroxyflavone (10 ± 1 µM), biochanin A (12 ± 5 µM), galangin (95 ± 28 µM), and genistein (123 ± 8 µM); baicalein showed no inhibition up to 50 µM.
- Isoflavones were poorer aromatase inhibitors than flavones; biochanin A inhibited better than genistein, which the authors attribute to its C4′-methoxy rather than C4′-hydroxy substituent.
- Mutations altered inhibitor potency in ways that supported the proposed binding pose: for example, chrysin Ki fell from 2.6 ± 0.1 µM in wild type to 0.3 ± 0.1 µM in I133Y, 0.6 ± 0.1 µM in I395F, and 0.06 ± 0.02 µM in I474Y, but rose to 13 ± 3 µM in D309A.
- Modeling and inhibition profiles indicated that flavones bind with rings A and C mimicking steroid rings D and C, respectively, and with the C4-keto group oriented toward the heme; 5-hydroxy, 3-hydroxy, and C6 substituents reduce binding, while the isoflavone 4′-hydroxy group also weakens aromatase inhibition.
Methods
- Inhibition kinetics were measured for eight phytoestrogens on wild-type human aromatase and six mutants (I133Y, P308F, D309A, T310S, I395F, I474Y) expressed in Chinese hamster ovary cells, using a ³H₂O release assay with 100 nM radiolabeled androstenedione and Ki values derived from Dixon plots.
- Mutants were generated by PCR-based site-directed mutagenesis, stably expressed in CHO cells, and confirmed by enzyme activity and western blot or immunoprecipitation analysis.
- Computer modeling used a previously generated human aromatase homology model; compounds were placed in the active site and energy minimized first with a rigid pocket and then allowing active-site residue movement.
Limitations
- The paper states that this is an in vitro study and that in vivo effects could differ because of metabolic conversion; cell culture and animal studies were described as initiated but not reported here.
- The paper states that the biphasic inhibition profiles observed for galangin in wild-type and some mutants are not understood, and that possible interaction with other CHO proteins cannot explain why only some mutant forms showed this pattern.
- The paper notes that naringenin Ki values may reflect a racemic mixture, so the S-configuration isomer may have lower actual Ki; evident from the text, the conclusions also depend on a homology-based computational model and a limited set of six mutants, and baicalein was not tested against mutants because it did not inhibit wild-type aromatase up to 50 µM.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These compounds were found to bind to the active site of aromatase in an orientation in which rings A and C mimic rings D and C of the androgen substrate, respectively.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among these compounds, the C4-keto group of genistein is the far- thest from the heme as seen in the model (Fig. 2D)”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Rests on an assumption: The computer model of the aromatase active site accurately represents the enzyme's active site and the binding orientations of the compounds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the presence of a single bond between the C-2 and C-3 positions does slightly modify the conformation of ring C (as shown by the computer model- ing)”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The computer model of the aromatase active site accurately represents the enzyme's active site and the binding orientations of the compounds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The C4-keto group of chrysin points towards the heme prosthetic group (Fig. 2C).”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As indicated in Figure 4, com- puter modeling suggests another possible orientation for the binding of flavone to the active site of aromatase, an orientation in which rings A and C of flavone mimics rings A and B of a steroid and the p-phenyl substituent is directed towards Ile-133.”
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“A confor- mational change in the active site by con- verting Ile-133 to Tyr increases the relative binding affinity of chrysin, as indicated by a decrease in the Ki value.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Computer modeling suggests that the phenyl sub- stituent of biochanin A is almost 900 rela- tive to the plane of chrysin's ring B (Fig. 2D)”
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The computer model of the aromatase active site accurately represents the enzyme's active site and the binding orientations of the compounds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Naringenin is slightly less potent than chrysin, but the inhibition profiles of narin- genin were found to be similar to those of chrysin.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“this agrees with our inhibi- tion experiment, which indicates that P- naphthoflavone is a very poor inhibitor (results not shown).”
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“7- Hydroxy- and 8-hydroxy-containing flavones are reasonable inhibitors of aro- matase.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and its Ki values are not different from those of the aromatase inhibitor AG (1.37 gM).”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“A smaller KJ value of a-naphthoflavone for P308F than the wild-type aromatase suggests further that the binding orientation of a-naph- thoflavone is slightly different from that of chrysin.”
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The potency of these compounds as aromatase inhibitors has been determined according to their K. values: a-naphthoflavone (2.2 ? 0.1 pM) >chrysin (2.6 ? 0.1 gM) >naringenin (5.1 ? 0.2 IM) >7,8-dihydroxyflavone (10 ? 1 1iM) >biochanin A (12 ? 5 pM) >galangin (95 ? 28 piM) >genistein (123 ? 8 pM).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The results for galangin indicate that the presence of a hydroxyl group at posi- tion 3 of the flavone significantly reduces its ability to bind to aromatase.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Its binding was also improved by Ile-474 to Tyr, Ile- 133 to Tyr, and Ile-395 to Phe mutations.”
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Rests on an assumption: The inhibition profiles and Ki values measured in the assay directly reflect the binding affinity of the compounds to aromatase.
- Rests on an assumption: The site-directed mutations alter the active site pocket in the intended way without grossly disrupting the enzyme's overall structure.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“explaining why the binding affinity of biochanin A was found to decrease in mutants P308F, D309A, and T31OS.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The inhibition profiles and Ki values measured in the assay directly reflect the binding affinity of the compounds to aromatase.
- Rests on an assumption: The site-directed mutations alter the active site pocket in the intended way without grossly disrupting the enzyme's overall structure.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our computer modeling analysis places the C4-keto group of flavones in an area for the angular C19 of the androgen steroid.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“cx-Naphthoflavone is the best aromatase inhibitor among all the phytoestrogens studied [agreeing with find- ings from other laboratories (17,20)]”
What the sources say
- Not matchedcites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [20]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Not matched
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The p-phenyl substituent tilts approximately 300 in reference to rings A and C of the flavone (see Fig. 2B).”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“by having a methoxy rather than a hydroxyl group at the C4' position, biochanin A is a relatively better inhibitor of aromatase than genistein.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Since both chrysin and galangin bear the same A ring, the rela- tive potency of I1 33Y to wild-type aro- matase exerted by these compounds has been found to be comparable in the two compounds.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our inhibition studies have shown that T3 1OS is more sensitive to galangin than the wild-type aromatase at concentra- tions less than 150 pM (Fig. 5).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Isoflavones are less effective than flavones in inhibiting aromatase.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Such a model also explains why polyphenols such as epi- catechin and epigallocatechin, which are present in tea and do not have a keto group at the corresponding position, are not capa- ble of inhibiting aromatase (Kao et al., unpublished observations; these compounds were provided by C. S. Yang from the College of Pharmacy, Rutgers University).”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“in agreement with its poor inhibitory potency.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While 7,8-dihydroxyflavone was found to be a less potent inhibitor than chrysin”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Naringenin is slightly less potent than chrysin, but the inhibition profiles of narin- genin were found to be similar to those of chrysin.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among the four flavones tested, chrysin is the best inhibitor.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Flavone and isoflavone phytoestrogens are plant chemicals and are known to be competitive inhibitors of cytochrome P450 aromatase with respect to the androgen substrate.”
- Also stated in: § Materials and Methods · plain
“These compounds were shown to be competitive inhibitors of aromatase with respect to the androgen sub- strate.”
What the sources say
- Not matchedcites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [19]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [20]
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- Not matchedcites [21]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [22]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Materials and Methods · plain
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Some of these com- pounds such as chyrsin (5,7-dihydrox- yflavone) inhibit aromatase with N values similar to that of aminoglutethimide, an aromatase inhibitor used clinically to treat breast cancer.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The results obtained from inhibition profile studies indicate that the binding of genistein is improved by conformational changes upon mutations in the region Pro-308 to Thr-310.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The inhibition profiles and Ki values measured in the assay directly reflect the binding affinity of the compounds to aromatase.
- Rests on an assumption: The site-directed mutations alter the active site pocket in the intended way without grossly disrupting the enzyme's overall structure.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our computer modeling has revealed that only the S-configuration isomer can bind to the active site.”
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Rests on an assumption: The computer model of the aromatase active site accurately represents the enzyme's active site and the binding orientations of the compounds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In our study, some of the compounds are found to inhibit aro- matase with JK values in the micromolar range.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, an interaction with other proteins cannot explain why biphasic inhibition profiles were found for some but not all mutant forms of the enzyme.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“On the other hand, the pres- ence of a 4'-hydroxyl group has only a small influence on the binding of the compound, as indicated by similar inhibitory profiles as”
- Also stated in: § Discussion · plain
“chrysin for the mutants P308F, D309A, and T310S.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Also stated in: § Discussion · plain
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“The binding orientation of flavones and isoflavones in relation to steroids in the active site of aromatase is different to that proposed for their binding to the estrogen receptor (ER) (40,41).”
What the sources say
- Not matchedcites [40]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [41]
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Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Not matched
In the paper
“Ibrahim and Abul-Hajj (19) have reported that 6-hydroxyflavone is a signifi- cantly weaker inhibitor of aromatase than flavone.”
What the sources say
- Not matchedcites [19]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“P-Naphthoflavone has a structure very different from a-naph- thoflavone and does not fit in the active site of the enzyme; this agrees with our inhibi- tion experiment”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The results indicate that the binding affinity decreases by having a hydroxyl group at the C-8 instead of the C-5 position.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, it is proposed that the pres- ence of a hydroxyl group at the C-8 posi- tion may push the A ring of the flavone closer to heme or Ile-133, resulting in a great increase of the resistance of I133Y to this flavone.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“The expression of these enzyme mutants in transfected CHO cells was confirmed by enzyme activity measurement and western blot analysis (or immunoprecipitation analysis) (23,24,26,30).”
What the sources say
- Not matchedcites [23]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [24]
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- Not matchedcites [26]
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- Not matchedcites [30]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Phytoestrogens have been reported to be inhibitors of aromatase (18-22); therefore, these chemicals may function as chemopre- ventive agents by inhibiting aromatase/estro- gen biosynthesis in postmenopausal women.”
What the sources say
- Not matchedcites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [19]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [20]
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- Not matchedcites [21]
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- Not matchedcites [22]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The C-6 position of flavones is sit- uated in a very restricted area”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The computer model of the aromatase active site accurately represents the enzyme's active site and the binding orientations of the compounds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“According to our model, Ile-474 appears to be near the beta- face and lower edge of chrysin's p-phenyl ring.”
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“therefore, any flavones that have a C-6 substituent cannot bind to the enzyme.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“explaining why there was an increase in the K; value for I133Y by comparing it to that of chrysin.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results indicate that a conver- sion of C2, C3 double bond to a single bond has only a small effect on its binding when compared to chrysin.”
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This study also provides a molecular basis as to why isoflavones are significantly poorer inhibitors of aromatase than flavones.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These compounds bind to the active site in an orientation such that their A and C rings mimic rings D and C of the steroid, respectively.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The computer model of the aromatase active site accurately represents the enzyme's active site and the binding orientations of the compounds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The increased potency for I474Y might be due to favorable aromatic-aromat- ic interactions between the phenyl sub- stituent and the mutated residue.”
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A smaller KJ value of a-naphthoflavone for P308F than the wild-type aromatase suggests further that the binding orientation of a-naph- thoflavone is slightly different from that of chrysin.”
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In combination with computer modeling, the binding characteristics and the structure requirement for flavone and isoflavone phytoestrogens to inhibit human aromatase were obtained.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The C4-keto group points to the heme prosthetic group.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The computer model of the aromatase active site accurately represents the enzyme's active site and the binding orientations of the compounds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“If a larger accessible volume of the binding cav- ity is obtained by removing the methyl group of threonine at position 310, galan- gin could bind better in the resulting active site.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These isoflavones cannot bind to aromatase in an orientation in which rings A and C mimic rings A and B of the steroid because the 4'- hydroxy group will be situated in the area equivalent to the C-6 position in flavones.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“again indicating that the 4-keto group is essential for the inhibition of aromatase.”
What the sources say
- Not matchedcites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Not matched
In the paper
“Kellis and Vickery (18) observed that removal of the C4-keto group of 7,8-benzoflavone's pyra- none C-ring to a furan ring totally dimin- ished the inhibition ability”
What the sources say
- Not matchedcites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, the increased sensitivity of T310S to chrysin suggests that in the normal enzyme this methyl group may be involved in steric dashes with the inhibitor, reducing its bind- ing affinity somewhat.”
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“Ibrahim and Abul-Hajj (19) report- ed that a reduction of the C4-keto group to a hydroxyl group greatly decreased the inhibitory potency.”
What the sources say
- Not matchedcites [19]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Furthermore, in the latter orientation, the C4-keto group would be away from the heme, making it difficult to explain the results associated with this substituent (18,19).”
What the sources say
- Not matchedcites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [19]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings indicate that the region around the C-6 position in the active site of aromatase must be very restricted.”
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our computer modeling reveals that isoflavones may enter the active site pocket in a similar way as flavones in that ring B is positioned near the distal helix and the C4- keto group is pointing towards the heme (see Fig. 2D).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The computer model of the aromatase active site accurately represents the enzyme's active site and the binding orientations of the compounds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, a 3-hydroxy group significantly changes the orientation of ring B, resulting in a large decrease in the ability to inhibit aromatase.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Isoflavones such as genistein and daidzein have the 4'-hydroxyphenyl group at posi- tion C-3, greatly reducing the ability to bind and inhibit aromatase.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Computer modeling suggests that the pocket on the distal helix side may be more compact or rigid so that ring B of chrysin and the two isoflavones have to be held at about the same position.”
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Rests on an assumption: The computer model of the aromatase active site accurately represents the enzyme's active site and the binding orientations of the compounds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Replacement by a bulkier residue such as tyrosine may cause a displacement of the heme, probably exerting an indirect effect on the bindings of flavones.”
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, in the present study, we reveal the different structural features for phytoestrogens bind- ing to aromatase and estrogen receptor.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“The results indicate that isoflavones such as genistein and biochanin A bind to ER 5-10 times stronger than flavones such as chrysin and flavanones such as naringenin.”
What the sources say
- Not matchedcites [42]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the present study provides a molecular basis regarding the binding nature and structural requirements of phytochemicals to inhibit aromatase.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- Probably not a substantial claim. 16
- It may state two separate claims as one. 19
- The quote only partly states this claim. 1
None of the sources cited for this claim have been checked yet.
In the paper
“In a recently completed experiment, 7- hydroxyflavone was found to be four times more potent than chrysin (Kao et al., unpublished results).”
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“By doing so, the p-phenyl sub- stituent (i.e., ring B) of chrysin is oriented in a similar position to that of the substrate's ring A and is directed towards Asp 309.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No inhibi- tion by baicalein was observed with concen- trations up to 50 pM.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe quote only partly states this claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Because 7,8- dihydroxyflavone has the same p-phenyl substituent as chrysin, the relative respons- es to P308F, D309A, T310S, and I474Y were found to be similar to chrysin.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“a-Naphthoflavone, but not P-naph- thoflavone, is a good inhibitor of aromatase.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Contrary to chrysin and other flavones, galangin binds relatively better to the mutant D309A than to the wild-type enzyme, sug- gesting that galangin fits better in the active site with a Asp-309 to Ala mutation.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“This may also explain why 4'- amino-6-hydroxyflavone is a very ineffec- tive inhibitor of aromatase (Kao et al., unpublished results).”
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Two types of inhibition profiles were observed for this compound; three mutants with changes located on the distal helix (P308F, D309A, and T310S) exhibited regular dose-dependent profiles, while the other three mutants as well as the wild-type enzymes exhibited unusual biphasic profiles (Fig. 5).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“For ER, isoflavones were found to be better ligands than flavones”
What the sources say
- Not matchedcites [40]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [41]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“As suggested previously (30), Pro-308 to Phe and Asp- 309 to Ala mutations modify the size of the active site pocket, thus preventing the bind- ing of chrysin as indicated by increases in the Ki values (Table 1).”
What the sources say
- Not matchedcites [30]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Computer modeling has revealed that the 3-hydroxyl group is pointing to the I-helix and affects the orientation of the phenyl substituent at the C-2 position and may also interfere with the interaction of the 4-keto group with the heme.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When superimposed over the structure of chrysin, the C4-keto group of a-naphthoflavone points closer to the heme, implying a better fit in the active site of aromatase (see Fig. 2C).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The computer model of the aromatase active site accurately represents the enzyme's active site and the binding orientations of the compounds.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Furthermore, a 4'-hydroxy group is thought to be required to bind ER effec- tively (see Fig. 6).”
What the sources say
- Not matchedcites [40]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [41]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“rings A and C of isoflavones were thought to mimic rings A and B of estrogen.”
What the sources say
- Not matchedcites [40]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [41]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“This 3H20 release assay for human aromatase expressed in CHO cells was previously vali- dated by the product isolation assay (33).”
What the sources say
- Not matchedcites [33]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, the opposite side of the pocket is compara- tively spacious (e.g., a-naphthoflavone binds stronger in the active site of aro- matase) and therefore allows the benzopyra- none rings of these compounds relatively free movement.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The computer model of the aromatase active site accurately represents the enzyme's active site and the binding orientations of the compounds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, this binding orientation is thought to be unfavorable because the mutant I133Y has been found to be more resistant to 7,8-dihydroxyflavone than the wild-type aromatase, whereas the same mutant is more sensitive to chrysin than the wild-type aromatase.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, the observed Ki values might originate from a racemic mixture and the actual Ki values for the S-configuration isomer may be lower than those shown in Table 1.”
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Estrogen synthesized by the tumor aromatase was shown to stimulate breast tumor growth in both an autocrine and a paracrine manner (15).”
What the sources say
- Not matchedcites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“In estrogen-dependent breast tumors, estrogens induce the expression of peptide growth factors that are responsible for the proliferative responses of cancer cells (11,12).”
What the sources say
- Not matchedcites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The presence of a 5-hydroxy group reduces the binding affinity, probably by forming a hydrogen bond with the 4-keto group.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ile-133 has been proposed to be sit- uated close to the heme in the current model.”
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As predict- ed from the computer model, the increased potency of galangin for I474Y may be due to a favorable aromatic-aromatic interac- tion between the p-phenyl substituent and the mutated residue.”
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The 5-hydroxy group probably forms an intramolecular hydrogen bonding with the 4-keto group [indicated by nuclear magnetic resonance (NMR) analysis (39)], weakening the inter- action of the 4-keto group with the heme.”
What the sources say
- Not matchedcites [39]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Cell culture and nude mouse studies using aromatase-transfected MCF-7 and T-47D cells (13-15) have demonstrated that tumor aromatase can play a role in breast cancer maintenance and progression.”
What the sources say
- Not matchedcites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ile-395 is assigned to lie at the far end of the hydrophobic pocket, and an aromatic-aro- matic interaction may also explain the increased potency by the mutation Ile-395 to Phe.”
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“It has been reported that 5-hydrox- yflavone is a less potent inhibitor of aro- matase than flavone (19).”
What the sources say
- Not matchedcites [19]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Phytoestrogens are plant chemicals that bind to the estrogen receptor and induce many components of estrogen action (2-10).”
What the sources say
- Not matchedcites [2]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [3]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [5]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [6]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [7]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The 3-hydroxyl group of galangin and Thr-310 of the enzyme are thought to be on the same side of the beta-face of the flavone's ring-C.”
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, we feel that this possibility is unlikely, or at least the cytochrome P450 reductase inhibition does not play a major role here because the inhibition profiles do vary for different aromatase mutants.”
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The IC50 values (i.e., the con- centration of the ligand competitor at which the binding of radiolabeled 17p- estradiol to the hER was reduced to 50%) for coumestrol, genistein, biochanin A, chrysin, and naringenin were determined as 0.01 pM, 2.0 pM, 6.0 pM, 33 pM, and 45 pM, respectively (42).”
What the sources say
- Not matchedcites [42]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The present study is an in vitro study. The effects could be different in vivo due to metabolic conversion processes.”
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Since we have found that flavones are known to be competitive inhibitors of NAD(P)H: quinone acceptor oxidoreductase with respect to NAD(P)H (43)”
What the sources say
- Not matchedcites [43]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
The paper relies on this without support.
The molecular basis of phytoestrogen inhibition of aromatase is not known.
“While phytoestrogens have been reported to be inhibitors of aromatase, the molecular basis of their inhibition of aromatase is not known.”
The authors state this as an assumption.
The active site pocket of aromatase is rigid during initial modeling.
“assuming that the pocket was rigid.”
The authors state this as an assumption.
Residues within the active site can move to better accommodate inhibitors (induced fit).
“assuming that residues within the active site can move to better accommodate the inhibitors (induced fit theory of molecular interaction)”
The paper relies on this without support.
The computer model of the aromatase active site accurately represents the enzyme's active site and the binding orientations of the compounds.
“Our computer modeling has revealed that only the S-configuration isomer can bind to the active site.”
“Computer modeling suggests that the pocket on the distal helix side may be more compact or rigid so that ring B of chrysin and the two isoflavones have to be held at about the same position.”
The paper relies on this without support.
The inhibition profiles and Ki values measured in the assay directly reflect the binding affinity of the compounds to aromatase.
“The results obtained from inhibition profile studies indicate that the binding of genistein is improved by conformational changes upon mutations in the region Pro-308 to Thr-310.”
The paper relies on this without support.
The site-directed mutations alter the active site pocket in the intended way without grossly disrupting the enzyme's overall structure.
“Its binding was also improved by Ile-474 to Tyr, Ile- 133 to Tyr, and Ile-395 to Phe mutations.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“several studies demonstrated that some component of alcoholic beverages, such as procyanidin B and phytoestrogens (i.e., flavones and isoflavones) could bind the active site of aromatase, leading to functional dysregulations.[133][134][135]”
From The chronic alcohol consumption influences the gonadal axis in men: Results from a meta‐analysis (2024) · cites this paper as [135]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Genistein's reported ER-binding advantage exceeds the stated range
MinorThe stated IC50 values are 2.0 pM for genistein and 33 pM for chrysin. Their ratio is 16.5, outside the stated 5-10-fold range.
Reported 10 · recomputed 16.5
“The results indicate that isoflavones such as genistein and biochanin A bind to ER 5-10 times stronger than flavones such as chrysin and flavanones such as naringenin.”
Citations
Cites
Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence.
Block, G., Patterson, B. H., & Subar, A. (1992) · Nutrition and Cancer · doi:10.1080/01635589209514201 · Cited by 3,321
Techniques of flavonoid identification.
Markham, K. R. (1982) · Academic Press eBooks · Cited by 1,255
Crystal Structure of Hemoprotein Domain of P450BM-3, a Prototype for Microsomal P450's
Ravichandran, K. G., Boddupalli, S. S., Hasermann, C. A., Peterson, J. A., & Deisenhofer, J. (1993) · Science · doi:10.1126/science.8342039 · Cited by 879
The 2.6-A crystal structure of Pseudomonas putida cytochrome P-450.
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Dietary flavonoids: effects on xenobiotic and carcinogen metabolism.
Moon, Y., Wang, X., & Morris, M. (2006) · Toxicology in Vitro · doi:10.1016/j.tiv.2005.06.048 · Cited by 883
Flavan‐3‐ols: Nature, occurrence and biological activity
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Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450.
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Shanle, E. K., & Xu, W. (2010) · Chemical Research in Toxicology · doi:10.1021/tx100231n · Cited by 521
Metadata
- Authors
- Kao, Y. C., Zhou, C., Sherman, M., Laughton, C. A., & Chen, S.
- Affiliations
- Beckman Research Institute (US)
- ORCID
- Laughton, C A
- Venue
- Environmental Health Perspectives
- Publisher
- American Chemical Society (ACS)
- Published
- 1998-02
- Volume
- 106
- Issue
- 2
- Pages
- 85-92
- ISSN
- 0091-6765 (ISSN-L)
- 1552-9924
- PMC
- PMC1533021
- OpenAlex
- W2008151923
- Cited by
- 338
- References
- 46
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 5 · 2023: 9 · 2022: 5 · 2021: 14 · 2020: 11 · 2019: 5 · 2018: 7 · 2017: 11 · 2016: 9 · 2015: 7 · 2014: 9 · 2013: 17 · 2012: 10
- FWCI
- 9.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- Locations
- Environmental Health Perspectives (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA044735, CA 44735)
- National Institute of Environmental Health Sciences (ES-08258, R01ES008258)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Phytoestrogen effects and research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Health Sciences › Medicine › Pharmacology (medical) › Flavonoids in Medical Research
- Keywords
- phytoestrogens, flavones, isoflavones, flavanones, naphthoflavone, competitive inhibition, chrysin, baicalein, galangin, genistein, biochanin A, naringenin, active site binding, structure-activity relationship, estrogen synthesis
- MeSH terms
- Animals, Aromatase, Binding Sites, Enzyme Inhibitors, Estrogens, Non-Steroidal, Flavonoids, Cricetinae, Isoflavones, Models, Molecular, Plants, Mutagenesis, Site-Directed, CHO Cells, Reverse Transcriptase Polymerase Chain Reaction, Plant Preparations, Aromatase Inhibitors, Phytoestrogens
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-02, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-02 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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