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Nicotine, cotinine, and anabasine inhibit aromatase in human trophoblast in vitro.
Open accessAbstract
Epidemiologic studies suggest that women who smoke have lower endogenous estrogen than nonsmokers. To explore the possible link between cigarette smoking and decreased endogenous estrogens, we have examined the effects of constituents of tobacco on estrogen production in human choriocarcinoma cells and term placental microsomes. In choriocarcinoma cell cultures, nicotine, cotinine (a major metabolite of nicotine), and anabasine (a minor component of cigarette tobacco) all inhibited androstenedione conversion to estrogen in a dose-dependent fashion. Removal of nicotine, cotinine, and anabasine from the culture medium resulted in the complete reversal of the inhibition of aromatase. In the choriocarcinoma cell cultures, a supraphysiologic concentration of androstenedione (73 microM) in the culture medium blocked the inhibition of aromatase caused by nicotine, cotinine, and anabasine. In preparations of term placental microsomes, nicotine, cotinine, and anabasine inhibited the conversion of testosterone to estrogen. Kinetic analysis demonstrated the inhibition to be competitive with respect to the substrate. These findings suggest that some nicotinic alkaloids directly inhibit aromatase. This mechanism may explain, in part, the decreased estrogen observed in women who smoke.
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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
“In the chorio- carcinoma cell cultures, a supraphysiologic concentration of an- drostenedione (73 ,M) in the culture medium blocked the in- hibition of aromatase caused by nicotine, cotinine, and anabasine.”
- Also stated in: § Effects ofnicotine, cotinine, and anabasine on estrogen accumulation in choriocarcinoma cell cultures · plain
“when the culture medium contained 73 1tM androstenedione, 30 ,M nicotine produced no inhibition of estradiol accumulation (Fig. 4).”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Effects ofnicotine, cotinine, and anabasine on estrogen accumulation in choriocarcinoma cell cultures · plain
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
“Aqueous extracts ofsmoke inhibited androstenedione conversion to estradiol in a dose-dependent manner (Fig. I A).”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Effects ofaqueous extracts ofcigarette smoke on estrogen accumulation in choriocarcinoma cell cultures
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
“Examination of the timecourse of nicotine inhibition of estradiol accumulation demonstrated that nicotine inhibited es- tradiol accumulation at the first timepoint examined, 1 h (Fig. 3).”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Effects ofnicotine, cotinine, and anabasine on estrogen accumulation in choriocarcinoma cell cultures
Strength:boosted· not yet calibratedCausal:direct· 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
“At con- centrations up to 150 ,uM, nicotine, cotinine, and anabasine did not alter cell number at the end of an 8-h incubation.”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Effects ofnicotine, cotinine, and anabasine on estrogen accumulation in choriocarcinoma cell cultures
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
“In contrast, at concentrations in the range offoot_2 mM, carbamylcholine, succinylcholine, hexamethonium, and decamethonium did not inhibit estradiol accumulation (Table III).”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Effects ofnicotine, cotinine, and anabasine on estrogen accumulation in choriocarcinoma cell cultures
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
“In contrast, when the culture medium contained 73 1tM androstenedione, 30 ,M nicotine produced no inhibition of estradiol accumulation (Fig. 4).”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Effects ofnicotine, cotinine, and anabasine on estrogen accumulation in choriocarcinoma cell cultures
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
“Nicotine in- hibited the accumulation of estradiol in a manner comparable to that observed in incubations of intact cells (data not shown).”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Effects ofnicotine, cotinine, and anabasine on estrogen accumulation in choriocarcinoma cell cultures
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
“In these three separate experiments the Kis for cotinine inhibition of aroma- tization were 15, 36, and 47 MuM (32.7±9.38 MM, mean±SEM) (Fig. 6).”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Effects ofnicotine, anabasine, and cotinine on aromatase activity in preparations ofterm placental microsomes
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
“Dialyzed smoke preparations (1,000 mol wt effective pore size) inhibited androstenedione conversion to estradiol in a dose- dependent manner (Fig. 1 B).”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Effects ofaqueous extracts ofcigarette smoke on estrogen accumulation in choriocarcinoma cell cultures
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
“In choriocarcinoma cell cultures, nicotine, cotinine (a major metabolite of nicotine), and anabasine (a minor component of cigarette tobacco) all inhibited androstenedione conversion to estrogen in a dose-dependent fashion.”
- Also stated in: § Effects ofnicotine, cotinine, and anabasine on estrogen accumulation in choriocarcinoma cell cultures · plain
“The addition of nicotine, cotinine, or anabasine to the chorio- carcinoma cell cultures inhibited estradiol accumulation in the media (Fig. 2).”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Effects ofnicotine, cotinine, and anabasine on estrogen accumulation in choriocarcinoma cell cultures · plain
- It may state two separate claims as one. 9
- Probably not a substantial claim. 5
- The quote only partly states this claim. 1
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 all experiments the accumulation ofestradiol always exceeded the accumulation of estrone, and the ratio of estradiol to estrone was in the range of 6:1-10:1.”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Characterization ofJar choriocarcinoma cell cultures
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ 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
“Addition ofandrostenedione to the choriocarcinoma cultures resulted in the appearance ofboth estradiol and estrone, but not testosterone or dihydrotestosterone.”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Characterization ofJar choriocarcinoma cell cultures
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
“The addition of nicotine to the choriocarcinoma cell cultures resulted in the inhibition of both estradiol and es- trone accumulation and a corresponding increase in unmetab- olized androstenedione (Table I).”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Effects ofnicotine, cotinine, and anabasine on estrogen accumulation in choriocarcinoma cell cultures
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
“Using radioactive progesterone and estradiol, partitioning experiments demonstrated that 95% of these two steroids were present in the culture medium and <5% in the explanted cells.”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Characterization ofJar choriocarcinoma cell cultures
Load-bearingStrength:boosted· 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
“Ad- dition of 1 MCi of [1,2-3H]progesterone or [6,7-3H]estradiol to 2 X I05 choriocarcinoma cells for 24 h resulted in the conversion of < 15% of the progesterone and <10% of the estradiol to other metabolites as determined by high performance liquid chro- matography.”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Characterization ofJar choriocarcinoma cell cultures
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
“At the doses used in this study, aqueous extracts of cigarette smoke did not inhibit progesterone accu- mulation or the cell number present in the culture.”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Effects ofaqueous extracts ofcigarette smoke on estrogen accumulation in choriocarcinoma cell cultures
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“The addition of aminoglutethimide to preparations ofplacental microsomes elicits a type II cytochrome P450 binding spectrum (20).”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Discussion
What the sources say
- Not checked — no full text of the sourcecites [20] 20. Meldrum, D. R., B. J. Davidson, I. V. Tataryn, and H. L. Judd. 1981. Changes in steroids with aging in postmenopausal women. Obstet. Gynecol. 57:624-628.
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.
In the paper
“Kellis and Vickery have reported that naturally occurring plant flavones are potent in- hibitors of aromatase (21).”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Discussion
What the sources say
- Not checked — no full text of the sourcecites [21] 21. Graves, P. E., and H. A. Salhanick. 1979. Stereoselective inhibition of aromatase by enantiomers of aminoglutethimide. Endocrinology. 105: 52-57. source
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.
In the paper
“In placental microsomal preparations, aminoglutethimide competitively inhibits the aromatization of testosterone with an ap- parent Ki of 14 ,uM (20).”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > Discussion
What the sources say
- Not checked — no full text of the sourcecites [20] 20. Meldrum, D. R., B. J. Davidson, I. V. Tataryn, and H. L. Judd. 1981. Changes in steroids with aging in postmenopausal women. Obstet. Gynecol. 57:624-628.
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.
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 the intrafollicular concentration of nicotine plus cotinine were 5 gM, the ratio of nicotine plus cotinine to androstenedione would be 2:1.This ratio is too low to produce significant inhi- bition.”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > MacMahon et al.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“However, the intrafollicular concentration of androstenedione is -500 times greater, 2.5 ,M (30).”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > MacMahon et al.
What the sources say
- Not checked — no full text of the sourcecites [30] 30. Goodman, A. L., and G. D. Hodgen. 1983. The ovarian triad of the primate menstrual cycle. Recent Prog. Horm. Res. 39:1-73. source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Jensen et al. have recently reported that in postmenopausal women, smoking may increase the metabolic clearance rate of estradiol (31).”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > MacMahon et al.
What the sources say
- Not checked — no full text of the sourcecites [31] 31. McNatty, K. P., D. M. Smith, A. Makris, R. Osathanondh, and K. J. Ryan. 1979. The microenvironment of the human antral follicle: interrelationships among the steroid levels in antral fluid, the population of granulosa cells, and the status of the oocyte in vivo and in vitro. J. Clin. Endocrinol. Metab. 49:851-860. source
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.
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 the corpus luteum is exposed to a nicotine plus cotinine concentration of 5 gM, then the ratio of nicotine plus cotinine to androstenedione would be 1,000:1.This high ratio could produce significant inhibition of the aro- matase system and a decrease in estrogen production.”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > MacMahon et al.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one. The quote only partly states this claim.
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 aromatase en- zyme system in the cells comprising the corpus luteum is probably exposed to an androstenedione concentration similar to that in the circulation, 5 nM.”
§ Nicotine, Cotinine, and Anabasine Inhibit Aromatase in Human Trophoblast In Vitro > MacMahon et al.
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
- Rests on an assumption: In the follicular phase of the menstrual cycle, the circulating androstenedione concentration is approximately 5 nM.
- Rests on an assumption: In the luteal phase of the menstrual cycle, the basement membrane of the dominant follicle is disrupted and the follicular microenvironment is lost.
The authors state this as an assumption.
The aromatase enzyme system in human granulosa cells is similar to placental aromatase.
“If the granulosa cell and placental aromatase are similar, then the in vitro observation that nicotine and cotinine”
The paper relies on this without support.
The concentrations of nicotine and cotinine in body fluids reflect their concentrations at the aromatase enzyme site in ovarian or placental tissues.
“The nicotine and cotinine concentrations present in ovarian follicular fluid and in steroidogenic tissues of women who smoke have not been reported.However, the concentrations of nicotine and cotinine that have been re- ported to be present in the body fluids of women who smoke suggests that the in vitro findings reported here may have relevance in vivo.”
The paper relies on this without support.
In the follicular phase of the menstrual cycle, the circulating androstenedione concentration is approximately 5 nM.
“In the follicular phase of the menstrual cycle, the circulating androstenedione concentration is -5 nM.”
The paper relies on this without support.
In the luteal phase of the menstrual cycle, the basement membrane of the dominant follicle is disrupted and the follicular microenvironment is lost.
“In contrast, in the luteal phase of the menstrual cycle, the basement membrane of the dominant follicle is disrupted, and the follicular microenvironment is lost.”
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In the citing paper
“First, nicotine, cotinine, and anabasine inhibit the aromatase enzyme, also called estrogen synthase, in a reversible manner and suppress the production of estrogen [56].”
From The Effect of Tobacco Smoking on Bone Mass: An Overview of Pathophysiologic Mechanisms (2018) · cites this paper as [56]
In the citing paper
“nicotine and cotinine suppress aromatase enzyme activity, contributing to a reduction in estrogen levels [54]”
From An Overlooked Bone Metabolic Disorder: Cigarette Smoking-Induced Osteoporosis (2022) · cites this paper as [54]
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Metadata
- Authors
- Barbieri, R. L., Gochberg, J., & Ryan, K. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1986-06-01
- Volume
- 77
- Issue
- 6
- Pages
- 1727-1733
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC370526
- OpenAlex
- W2115000106
- Semantic Scholar
- fe8ede07340192b572ab17ad21fdf2e3ea0e5789
- Cited by
- 197
- References
- 35
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 1 · 2022: 8 · 2021: 5 · 2020: 5 · 2019: 3 · 2018: 10 · 2017: 6 · 2016: 4 · 2015: 4 · 2014: 9 · 2013: 5 · 2012: 13
- FWCI
- 3.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD18292)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Smoking Behavior and Cessation
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- nicotine, cotinine, anabasine, aromatase inhibition, tobacco smoke, estrogen synthesis, choriocarcinoma cells, placental microsomes, androstenedione, testosterone, competitive inhibition, endogenous estrogen
- MeSH terms
- Anabasine, Androstenedione, Carbachol, Cells, Cultured, Choriocarcinoma, Cotinine, Decamethonium Compounds, Dose-Response Relationship, Drug, Estradiol, Female, Hexamethonium Compounds, Humans, Kinetics, Microsomes, Nicotine, Piperidines, Placenta, Pregnancy, Pyrrolidinones, Smoking, Succinylcholine, Trophoblasts, Uterine Neoplasms, Aromatase Inhibitors, In Vitro Techniques
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