The DOI matches its Crossref record; 150 of the 150 references it cites were found in a registry or an index; none of the 187 sources its claims cite is checked for support yet.
Antioxidant Protective Mechanisms against Reactive Oxygen Species (ROS) Generated by Mitochondrial P450 Systems in Steroidogenic Cells
Abstract
Mitochondrial P450 type enzymes catalyze central steps in steroid biosynthesis, including cholesterol conversion to pregnenolone, 11beta and 18 hydroxylation in glucocorticoid and mineralocorticoid synthesis, C-27 hydroxylation of bile acids, and 1alpha and 24 hydroxylation of 25-OH-vitamin D. These monooxygenase reactions depend on electron transfer from NADPH via FAD adrenodoxin reductase and 2Fe-2S adrenodoxin. These systems can function as a futile NADPH oxidase, oxidizing NADPH in absence of substrate, and leak electrons via adrenodoxin and P450 to O(2), producing superoxide and other reactive oxygen species (ROS). The degree of uncoupling depends on the P450 and steroid substrate. Studies with purified proteins and overexpression in cultured cells show consistently that adrenodoxin, but not reductase, is responsible for ROS production that can lead to apoptosis. In the ovary and corpus luteum, antioxidant enzyme activities superoxide dismutase, catalase, and glutathione peroxidase parallel steroidogenesis. Antioxidant beta-carotene, alpha-tocopherol, and ascorbate can protect against oxidative damages of P450 systems. In testis Leydig cells, steroidogenesis is associated with aging of the steroidogenic capacity.
Overview
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Written from the paper’s full text.
TL;DR
This review synthesizes evidence that mitochondrial P450 systems in steroidogenic cells can leak electrons to O₂, generating ROS, with adrenodoxin as a key mediator and P450c11 more uncoupled than P450scc. It describes antioxidant defenses—SOD, catalase, glutathione peroxidase, ascorbate, tocopherol, and β-carotene—that parallel steroidogenesis and can protect against oxidative damage.
Key findings
- Reconstituted bovine mitochondrial P450 components act as a futile NADPH oxidase: AdR alone had O₂ reduction <0.001 mol e⁻/min/mol AdR, but AdR + adrenodoxin increased to 149 ± 34, and AdR + adrenodoxin + P450scc increased further to 721 ± 125 mol e⁻/min/mol AdR.
- P450c11 is much more leaky than P450scc: in reconstituted systems, at most 15% of total electron flow in the P450scc system went to ROS formation, whereas 32–43% of electrons were consumed in ROS generation by P450c11.
- Adrenodoxin, not adrenodoxin reductase, appears responsible for ROS production leading to apoptosis: overexpression of human or bovine adrenodoxin decreased cell viability in all 11 cell lines tested, while an apo-mutant adrenodoxin (C46S) lacking the 2Fe-2S cluster did not cause apoptosis; AdR overexpression alone did not increase ROS or apoptosis.
- Antioxidant enzyme activities parallel steroidogenesis: in bovine corpora lutea, SOD and catalase activities peak at about day 16 of the estrous cycle and then drop in parallel with P450scc and adrenodoxin levels; ascorbate concentrations are highest in steroidogenic tissues such as adrenal cortex and corpus luteum.
Methods
- Narrative review of published studies on mitochondrial P450 systems, ROS generation, and antioxidant protection in steroidogenic cells.
- Evidence reviewed includes reconstituted systems with purified bovine mitochondrial P450 proteins, cultured-cell overexpression experiments, and animal tissue studies of adrenal cortex, ovary/corpus luteum, and testis Leydig cells.
- Main analysis is qualitative synthesis, supported by tables of electron-transfer rates, redox potentials, steroid effects on P450c11 leakage, and antioxidant levels in steroidogenic tissues.
Limitations
- The paper states that its summary points apply to the specific cases reviewed and “do not represent general rules for all mitochondrial P450 and antioxidant combinations in different systems.”
- The paper notes that there is currently no precise information on absolute concentrations of NADH and NADPH in the mitochondrial matrix where steroidogenic enzymes are located.
- Evident from the text: this is a narrative review without a systematic search or meta-analysis, and it compares findings across different species, tissues, temperatures, and cell models; the paper also acknowledges that adrenodoxin overexpression conclusions may be questioned because those studies used non-steroidogenic cells.
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Claims the paper makes
141 Not checked yet · 46 Own interpretation · 10 No basis given
None of the sources cited for this claim have been checked yet.
In the paper
“Studies with purified proteins and overexpression in cultured cells show consistently that adrenodoxin, but not reductase, is responsible for ROS production”
What the sources say
- Not checked yetcites Hanukoglu et al., 1993
- Not checked yetcites Rapoport et al., 1995
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Addition of adrenodoxin greatly stimulates the rate of NADPH oxidation and O 2 reduction.”
What the sources say
- Not checked yetcites Hanukoglu et al., 1993
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“Thus, even if these P450 systems leak electrons at a low rate, their total capacity for free radical generation could be high, especially in steroidogenic tissues.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“P450scc system produced less H 2 O2 during cholesterol substrate hydroxylation than that observed in the absence of substrate.”
What the sources say
- Not checked yetcites Rapoport et al., 1995
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In adrenal mitochondria the concentrations of P450scc and adrenodoxin are similar”
What the sources say
- Not checked yetcites Hanukoglu and Hanukoglu, 1986
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In the paper
“ESR assays using a spin trap and other assays provided further evidence that leaking electrons react with O 2 to produce superoxide radical”
What the sources say
- Not checked yetcites Hanukoglu et al., 1993
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In the paper
“These systems can function as a futile NADPH oxidase, oxidizing NADPH in absence of substrate”
- Also stated in: § Studies with Purified Enzymes · plain
“Experiments using purified mitochondrial P450 system proteins showed that these systems can oxidize NADPH in the absence of a steroid substrate”
What the sources say
- Not checked yetcites Hanukoglu et al., 1993
- Not checked yetcites Rapoport et al., 1995
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Studies with Purified Enzymes · plain
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
“Thus, the difference between the leakage rates of these P450s would be further magnified at 37 ° C reactions for P450c11.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In contrast, P450c11 system produced more H 2 O2 during substrate deoxycorticosterone metabolism”
What the sources say
- Not checked yetcites Rapoport et al., 1995
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In the paper
“Addition of either of these P450s increases superoxide production significantly above that observed by reductase and adrenodoxin couple”
What the sources say
- Not checked yetcites Hanukoglu et al., 1993
- Not checked yetcites Rapoport et al., 1995
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 33
- Probably not a substantial claim. 26
None of the sources cited for this claim have been checked yet.
In the paper
“In aerobic solution, adrenodoxin reductase that is reduced by NADPH remains reduced and does not readily oxidize by itself”
What the sources say
- Not checked yetcites Chu and Kimura, 1973
- Not checked yetcites Hanukoglu et al., 1993
- Not checked yetcites Sugiyama et al., 1979
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In the paper
“In contrast, 11 β -hydroxylated products of P450c11, and other steroids with a strict stereo-specificity, strongly stimulated electron leakage from P450c11, but not from P450scc”
What the sources say
- Not checked yetcites Rapoport et al., 1995
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In the paper
“Mitochondrial P450 type enzymes catalyze central steps in steroid biosynthesis, including cholesterol conversion to pregnenolone, 11 β and 18 hydroxylation in glucocorticoid and mineralocorticoid synthesis, C-27 hydroxylation of bile acids, and 1 α and 24 hydroxylation of 25-OH-vitamin D.”
What the sources say
- Not checked yetcites Hanukoglu, 1992
- Not checked yetcites Miller, 2005
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A study that examined ROS formation in reconstituted mitochondrial P450 systems revealed that both P450scc and P450c11 generate ROS during their catalytic function of steroid hydroxylation”
What the sources say
- Not checked yetcites Rapoport et al., 1995
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Adrenodoxin expression enhanced oxidation of dihydroethidium to ethidium, providing evidence for the generation of ROS in the cell lines.”
What the sources say
- Not checked yetcites Derouet-Humbert et al., 2005
plaindirectn = 11- Asserted: passes — The authors put it forward as true.
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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
“In steroidogenic cells there are no major vesicular stores of steroid products, as steroids are rapidly secreted into the blood stream after synthesis.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Cytochrome c aggregates with apoptosis-protease-activating factor 1 (Apaf-1), and procaspase-9 forming apoptosomes. Caspase-9 is cleaved and activated by the apoptosomes and then it activates downstream effector caspases (caspase-3 and -7), spreading a cascade of proteolytic activity that leads to digestion of structural proteins in the cytoplasm and eventual phagocytosis of the cell (Bras et al.”
What the sources say
- Not checked yetcites Bras et al., 2005
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The first step of steroid hormone biosynthesis in all steroidogenic tissues is the cleavage of the side-chain of cholesterol by P450scc that produces pregnenolone (Hanukoglu, 1992; Miller, 2005; Payne and Hales, 2004).”
What the sources say
- Not checked yetcites Hanukoglu, 1992
- Not checked yetcites Miller, 2005
- Not checked yetcites Payne and Hales, 2004
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“The addition of this steroid derivative induces apoptosis in human breast cancer MCF-7 cells by disruption of mitochondrial function, associated with cytochrome c release, and production of reactive oxygen species (Narvaez and Welsh, 2001; Narvaez et al., 2003).”
What the sources say
- Not checked yetcites Narvaez and Welsh, 2001
- Not checked yetcites Narvaez et al., 2003
plaindirect- Asserted: passes — The authors put it forward as true.
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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, experimental observations noted previously raise a caveat that steroidal drugs may have similar effects stimulating ROS production by steroid metabolizing enzymes.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Consistent with these findings, AdR over-expression by itself is not associated with increased ROS formation or ROS triggered apoptosis (Derouet-Humbert et al., 2005).”
What the sources say
- Not checked yetcites Derouet-Humbert et al., 2005
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In other P450 systems, various substrates and substrate analogs show wide variation in their effects on the coupling of the electron transfer process”
What the sources say
- Not checked yetcites Jung et al., 2002
- Not checked yetcites Shertzer et al., 2004a, 2004b
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Consistent with the process of apoptosis, overexpression of adrenodoxin was shown to disrupt mitochondrial transmembrane potential, indicating breakdown of the outer mitochondrial membrane and increased caspase activity in the cell (Derouet-Humbert et al., 2005).”
What the sources say
- Not checked yetcites Derouet-Humbert et al., 2005
plaindirect- Asserted: passes — The authors put it forward as true.
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It 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
“The steroids that have no effect on electron leakage may not enter into the substrate pocket of P450, or simply not affect the heme-O 2 interaction in the active site.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“leading the authors to conclude that 'difference in the availability of mitochondrial cholesterol might contribute to the observed tissue specificity of CYP11A1induced apoptosis' (Derouet-Humbert et al., 2005).”
What the sources say
- Not checked yetcites Derouet-Humbert et al., 2005
hedgedconditionaln = 11- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
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In the paper
“The loss of the activity of P450c11 is not accompanied by loss of steroid synthesis, indicating that P450scc continues to function with little or no damage under the same conditions.”
What the sources say
- Not checked yetcites Hornsby and Crivello, 1983
- Not checked yetcites Hornsby, 1980, 1989
hedged- Asserted: passes — The authors put it forward as true.
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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
“While cholesterol supply is regulated by 'on-off' switch type mechanisms, NADPH synthesis is regulated by mechanisms that function as a graded rheostat.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In bovine corpora lutea, a low but significant correlation was observed between mitochondrial P450 system enzymes and a cytochrome oxidase subunit (Hanukoglu and Hanukoglu, 1986).”
What the sources say
- Not checked yetcites Hanukoglu and Hanukoglu, 1986
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The rate of mitochondrial ROS generation is related to the level of oxidative damage to mtDNA and is inversely correlated with maximum longevity in higher vertebrates (Barja, 2004).”
What the sources say
- Not checked yetcites Barja, 2004
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In the placenta, a different START protein (MLN64) is involved in the transport of cholesterol to the mitochondria (Tuckey, 2005).”
What the sources say
- Not checked yetcites Tuckey, 2005
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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 these findings reflect normal physiological status, then adrenodoxin may be a source of ROS in absence of steroid metabolism.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Rests on an assumption: Cellular metabolism could have changed within minutes after induction of anesthesia and prior to removal of the adrenal.
None of the sources cited for this claim have been checked yet.
In the paper
“Chronic in vivo administration of ACTH in rats was observed to reduce plasma aldosterone, down-regulate CYP11B2 mRNA, and reduce P450aldo activity (Lehoux et al., 1998; Suwa et al., 2000).”
What the sources say
- Not checked yetcites Lehoux et al., 1998
- Not checked yetcites Suwa et al., 2000
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Chronic ACTH administration in rats increased Mn-SOD expression, but decreased glutathione peroxidase mRNA in the adrenal capsules (Raza et al., 2005; Suwa et al., 2000).”
What the sources say
- Not checked yetcites Raza et al., 2005
- Not checked yetcites Suwa et al., 2000
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In sheep corpora lutea, cytosolic Cu-Zn-SOD, mitochondrial Mn-SOD, and glutathione peroxidase activities rise while nitric oxide synthase (NOS) decreases during the luteal phase (Al-Gubory et al., 2005).”
What the sources say
- Not checked yetcites Al-Gubory et al., 2005
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The addition of an antioxidant drug, silibinin, at a low dose, potentiated ACTH-stimulated secretion of corticosteroids in hyperplastic adrenocortical cells, leading the authors to conclude that the effect of silibinin is presumably due to the antioxidant property of the drug (Racz et al., 1990).”
What the sources say
- Not checked yetcites Racz et al., 1990
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
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In the paper
“In contrast, at the stage of luteolysis, free radicals could play a functional role in apoptotic cell death and contribute to regression of corpus luteum (Behrman et al., 2001; Foyouzi et al., 2005; Niswender et al., 2000).”
What the sources say
- Not checked yetcites Behrman et al., 2001
- Not checked yetcites Foyouzi et al., 2005
- Not checked yetcites Niswender et al., 2000
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“In cultured ovarian cancer cells, ROS stress induced Mn-SOD expression; suppression of Mn-SOD expression by siRNA caused an increase in superoxide and promoted cell proliferation in vitro and tumor growth in vivo (Hu et al., 2005).”
What the sources say
- Not checked yetcites Hu et al., 2005
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“During the luteal phase, the increase in progesterone secretion reflects proliferation of steroidogenic cells and a major increase in the expression of the steroidogenic enzymes, primarily mitochondrial cholesterol side-chain cleavage P450scc.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In rats, vitamin A depletion causes a secondary deficiency of ascorbic acid in the adrenal, leading to adrenocortical degeneration, and ascorbate supplement prevents degeneration (Gruber et al., 1976).”
What the sources say
- Not checked yetcites Gruber et al., 1976
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“ACTH stimulated cortisol secretion from the guinea pig adrenal is accompanied by a decrease in the levels of ascorbate in the adrenal, but not in other tissues or plasma (Laney et al., 1990).”
What the sources say
- Not checked yetcites Laney et al., 1990
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“If there is no pregnancy, then corpus luteum regresses by an apoptotic process (McCracken et al., 1999; Niswender, 2002; Tilly, 1996; Zheng et al., 1994).”
What the sources say
- Not checked yetcites McCracken et al., 1999
- Not checked yetcites Niswender, 2002
- Not checked yetcites Tilly, 1996
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
“Thus, at the final stage of corpus luteum, antioxidant levels would be expected to decrease, allowing ROS to contribute to apoptosis and regression of the corpus luteum.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It 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
“The findings for the small antioxidant molecules show that the levels of these antioxidants change significantly during corpus luteum development, yet there does not appear to be a consistent pattern indicating complex functional and regulatory roles for these.”
hedged- Asserted: passes — The authors put it forward as true.
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It 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
“The findings reviewed in the following paragraphs for the antioxidant enzymes SOD, catalase, and glutathione peroxidase are, in general, consistent with these expected trends.”
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“However, while Cu-Zn-SOD activity and mRNA dropped during luteal regression, Mn-SOD activity and mRNA showed further increases, suggesting that these two enzymes play different roles in regulating luteal function (Sugino et al., 2000).”
What the sources say
- Not checked yetcites Sugino et al., 2000
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“After ovulation, the follicle enters the luteal phase, during which granulosa and theca cells of the follicle proliferate to form corpus luteum, and synthesize and secrete progesterone at high levels (nmol/L range) to prepare the uterus for implantation.”
What the sources say
- Not checked yetcites McCracken et al., 1999
- Not checked yetcites Niswender, 2002
- Not checked yetcites Tilly, 1996
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“In bovine corpus luteum, the levels of ascorbate increase during the luteal phase and then drop during regression (Rapoport et al., 1998).”
What the sources say
- Not checked yetcites Rapoport et al., 1998
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In rat ovary, follicular development was associated with an increase in vitamin A and luteal regression was associated with an increase in both vitamins A and E (Aten et al., 1992).”
What the sources say
- Not checked yetcites Aten et al., 1992
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“With aging in males, the capacity for testosterone biosynthesis declines as a consequence of multiple alterations in the hypothalamic-pituitary axis and Leydig cell steroidogenic system (Wang and Stocco, 2005; Zirkin and Chen, 2000).”
What the sources say
- Not checked yetcites Wang and Stocco, 2005
- Not checked yetcites Zirkin and Chen, 2000
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Exogenously added H 2 O2 was observed to inhibit both cAMP-stimulated progesterone production and StAR protein expression in MA-10 tumor Leydig cells, but did not effect P450scc enzyme levels (Diemer et al., 2003).”
What the sources say
- Not checked yetcites Diemer et al., 2003
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The Leydig cells develop and reach their full steroidogenic potential after puberty (Cummings and Kavlock, 2004).”
What the sources say
- Not checked yetcites Cummings and Kavlock, 2004
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
“Steroidogenic cells have a full spectrum of antioxidant molecules, which in some tissues reach the highest level in the body.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“| Vitamin A | Bovine | C. luteum | 3.5-5.5 μ g/g tissue | (Haliloglu et al., 2002) |”
What the sources say
- Not checked yetcites Haliloglu et al., 2002
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“| α -tocopherol | Rat | Adrenal | 30-50 μ g/g tissue | (Burczynski et al., 2001) |”
What the sources say
- Not checked yetcites Burczynski et al., 2001
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The findings of some studies provide evidence for the hypothesis that ROS produced as a by-product of steroidogenesis may be responsible for age-related decline in testosterone production by the Leydig cells (Chen and Zirkin, 1999; Zirkin and Chen, 2000).”
What the sources say
- Not checked yetcites Chen and Zirkin, 1999
- Not checked yetcites Zirkin and Chen, 2000
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“| Ascorbate | Rat | Adrenal | 2.5-5 mg/g tissue | (Mitani et al., 2005) |”
What the sources say
- Not checked yetcites Mitani et al., 2005
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Vitamin C is taken up into the cell by specific transporter proteins SVCT1 and SVCT2 (Wilson, 2005).”
What the sources say
- Not checked yetcites Wilson, 2005
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“| α -tocopherol | Bovine | C. luteum | 1-132 μ g/g tissue | (Rapoport et al., 1998) (Schweigert, 2003) |”
What the sources say
- Not checked yetcites Rapoport et al., 1998
- Not checked yetcites Schweigert, 2003
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The Leydig cells in the interstitium, located in between the seminiferous tubules of the testis, are the major source of androgenic steroids (Payne and Hales, 2004; Zirkin and Chen, 2000).”
What the sources say
- Not checked yetcites Payne and Hales, 2004
- Not checked yetcites Zirkin and Chen, 2000
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The fact that both adrenodoxin and P450 are metal carrying proteins that generate free radicals during electron transfer make these proteins prone to metal-catalyzed oxidation and crosslinking reactions (Liu et al., 2004; Stadtman, 1993).”
What the sources say
- Not checked yetcites Liu et al., 2004
- Not checked yetcites Stadtman, 1993
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“| Ascorbate | Bovine | C. luteum | 4-10 mg/g tissue | (Rapoport et al., 1998) |”
What the sources say
- Not checked yetcites Rapoport et al., 1998
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The addition of β -carotene at levels found in bovine serum, but not α -tocopherol or ascorbic acid, inhibited the cross-linking (Young et al., 1995).”
What the sources say
- Not checked yetcites Young et al., 1995
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“| β -carotene | Bovine | C. luteum | 6-216 μ g/g tissue | (Arikan and Rodway, 2001) (Haliloglu et al., 2002) |”
What the sources say
- Not checked yetcites Arikan and Rodway, 2001
- Not checked yetcites Haliloglu et al., 2002
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“and small antioxidants (Chen et al., 2005; Livera et al., 2002).”
What the sources say
- Not checked yetcites Chen et al., 2005
- Not checked yetcites Livera et al., 2002
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
AdR is ubiquitously expressed in different cells.
“AdR is ubiquitously expressed in different cells.”
The paper relies on this without support.
Mitochondrial P450 system electron transfer proteins are ubiquitously expressed in different tissues.
“Yet, the mitochondrial P450 system electron transfer proteins are ubiquitously expressed in different tissues.”
The paper relies on this without support.
The cells used in adrenodoxin overexpression studies are non-steroidogenic cells.
“This conclusion may be questioned, noting that the cells used in overexpression studies are non-steroidogenic cells.”
The paper relies on this without support.
Cellular metabolism could have changed within minutes after induction of anesthesia and prior to removal of the adrenal.
“This interpretation requires a caveat that cellular metabolism could have changed within minutes after induction of anesthesia and prior to the removal of the adrenal.”
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
“This electron transfer forms a high-affinity complex between the proteins17.”
From Impairing the interaction between Erg11 and cytochrome P450 reductase Ncp1 enhances azoles’ antifungal activities (2025) · cites this paper as [17]
Experimental — accuracy not yet measured
Citations
Cites
Mitochondrial formation of reactive oxygen species
Turrens, J. F. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2003.049478 · Cited by 5,084
Schafer, F. Q., & Buettner, G. R. (2001) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(01)00480-4 · Cited by 4,587
Oxidative DNA damage: mechanisms, mutation, and disease
Cooke, M. S., Evans, M. D., Dizdaroglu, M., & Lunec, J. (2003) · The FASEB Journal · doi:10.1096/fj.02-0752rev · Cited by 3,245
P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature
Nelson, D. R., Koymans, L. M. H., Kamataki, T., Stegeman, J. J., Feyereisen, R., Waxman, D. J., Waterman, M. R., Gotoh, O., Coon, M. J., Estabrook, R. W., et al. (1996) · Pharmacogenetics · doi:10.1097/00008571-199602000-00002 · Cited by 2,946
The Pecking Order of Free Radicals and Antioxidants: Lipid Peroxidation, α-Tocopherol, and Ascorbate
Buettner, G. R. (1993) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1993.1074 · Cited by 2,417 · cited 1×
“An important action of ascorbate as an antioxidant is the recycling of α-tocopheryl radical (Buettner, 1993; May, 1999; Rose and Bode, 1993).”
BackgroundOverview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones
Payne, A. H., & Hales, D. B. (2004) · Endocrine Reviews · doi:10.1210/er.2003-0030 · Cited by 1,766
Topology of superoxide production from different sites in the mitochondrial electron transport chain
St-Pierre, J., Buckingham, J. A., Roebuck, S. J., & Brand, M. D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m207217200 · Cited by 1,545
Stadtman, E. R. (1993) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.62.070193.004053 · Cited by 1,408
Mitochondrial metabolism of reactive oxygen species
Andreyev, A. Y., Kushnareva, Y. E., & Starkov, A. A. (2005) · Biochemistry (Moscow) · doi:10.1007/s10541-005-0102-7 · Cited by 1,336
Mechanisms Controlling the Function and Life Span of the Corpus Luteum
NISWENDER, G. D., Juengel, J. L., Silva, P. J., Rollyson, M. K., & McIntush, E. W. (2000) · Physiological Reviews · doi:10.1152/physrev.2000.80.1.1 · Cited by 1,076
Cited by
Sorted by citations
How mitochondria produce reactive oxygen species
Murphy, M. P. (2009) · Biochemical Journal · doi:10.1042/bj20081386 · Cited by 8,207
Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling.
Lee, J., Giordano, S., & Zhang, J. (2012) · Biochemical Journal · doi:10.1042/bj20111451 · Cited by 1,438
ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells
Snezhkina, A. V., Kudryavtseva, A. V., Kardymon, O. L., Savvateeva, M. V., Melnikova, N. V., Krasnov, G. S., & Dmitriev, A. A. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/6175804 · Cited by 934
Oxidative Stress in Human Pathology and Aging: Molecular Mechanisms and Perspectives
Hajam, Y. A., Rani, R., Ganie, S. Y., Sheikh, T. A., Javaid, D., Qadri, S. S., Pramodh, S., Alsulimani, A., Alkhanani, M. F., Harakeh, S., et al. (2022) · Cells · doi:10.3390/cells11030552 · Cited by 915
Azad, M. B., Chen, Y., & Gibson, S. B. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2270 · Cited by 764
Metadata
- Authors
- Hanukoglu, I.
- Affiliations
- Ariel University (IL)
- Corresponding author
- Hanukoglu, Israel
- ORCID
- Hanukoglu, Israel
- Venue
- Drug Metabolism Reviews
- Publisher
- Informa UK Limited
- Published
- 2006-01
- Volume
- 38
- Issue
- 1-2
- Pages
- 171-196
- ISSN
- 0360-2532 (ISSN-L)
- 1097-9883
- OpenAlex
- W2038758189
- Semantic Scholar
- e47d7fe29aa2374a673ae5d2f21edb3fbd816884
- Cited by
- 293
- References
- 150
- Citations by year
- 2026: 15 · 2025: 16 · 2024: 18 · 2023: 18 · 2022: 14 · 2021: 20 · 2020: 16 · 2019: 10 · 2018: 11 · 2017: 17 · 2016: 12 · 2015: 13 · 2014: 18 · 2013: 11 · 2012: 22
- FWCI
- 1.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- mitochondrial cytochrome P450, steroidogenesis, reactive oxygen species, oxidative stress, adrenodoxin, adrenodoxin reductase, superoxide production, antioxidant enzymes, superoxide dismutase, catalase, glutathione peroxidase, beta-carotene, alpha-tocopherol, vitamin C, Leydig cells, corpus luteum, ovary, steroidogenic cells
- MeSH terms
- Adrenodoxin, Animals, Antioxidants, Cytochrome P-450 Enzyme System, Electron Transport, Endocrine Glands, Humans, Mitochondria, NADP, Steroids, Reactive Oxygen Species
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 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (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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