Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1986 Jun;77(6):1727–1733. doi: 10.1172/JCI112494

Nicotine, cotinine, and anabasine inhibit aromatase in human trophoblast in vitro.

R L Barbieri, J Gochberg, K J Ryan
PMCID: PMC370526  PMID: 3711333

Abstract

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.

Full text

PDF
1727

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barbieri R. L., Canick J. A., Ryan K. J. Danazol inhibits steroidogenesis in the rat testis in vitro. Endocrinology. 1977 Dec;101(6):1676–1682. doi: 10.1210/endo-101-6-1676. [DOI] [PubMed] [Google Scholar]
  2. Barbieri R. L., Canick J. A., Ryan K. J. High-affinity steroid binding to rat testis 17 alpha-hydroxylase and human placental aromatase. J Steroid Biochem. 1981 Apr;14(4):387–393. doi: 10.1016/0022-4731(81)90158-8. [DOI] [PubMed] [Google Scholar]
  3. Baron J. A. Smoking and estrogen-related disease. Am J Epidemiol. 1984 Jan;119(1):9–22. doi: 10.1093/oxfordjournals.aje.a113730. [DOI] [PubMed] [Google Scholar]
  4. Benowitz N. L., Hall S. M., Herning R. I., Jacob P., 3rd, Jones R. T., Osman A. L. Smokers of low-yield cigarettes do not consume less nicotine. N Engl J Med. 1983 Jul 21;309(3):139–142. doi: 10.1056/NEJM198307213090303. [DOI] [PubMed] [Google Scholar]
  5. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  6. Canick J. A., Ryan K. J. Cytochrome P-450 and the aromatization of 16alpha-hydroxytestosterone and androstenedione by human placental microsomes. Mol Cell Endocrinol. 1976 Dec;6(2):105–115. doi: 10.1016/0303-7207(76)90010-1. [DOI] [PubMed] [Google Scholar]
  7. Challis J. R., Davies I. J., Benirschke K., Hendrickx A. G., Ryan K. J. The effects of dexamethasone on the peripheral plasma concentrations of androstenedione, testosterone and cortisol in the pregnant rhesus monkey. Endocrinology. 1975 Jan;96(1):185–192. doi: 10.1210/endo-96-1-185. [DOI] [PubMed] [Google Scholar]
  8. Challis J. R., Davies J., Ryan K. J. The concentrations of progesterone, estrone and estradiol-17 beta in the plasma of pregnant rabbits. Endocrinology. 1973 Oct;93(4):971–976. doi: 10.1210/endo-93-4-971. [DOI] [PubMed] [Google Scholar]
  9. Daniell H. W. Osteoporosis of the slender smoker. Vertebral compression fractures and loss of metacarpal cortex in relation to postmenopausal cigarette smoking and lack of obesity. Arch Intern Med. 1976 Mar;136(3):298–304. doi: 10.1001/archinte.136.3.298. [DOI] [PubMed] [Google Scholar]
  10. Goodman A. L., Hodgen G. D. The ovarian triad of the primate menstrual cycle. Recent Prog Horm Res. 1983;39:1–73. doi: 10.1016/b978-0-12-571139-5.50005-7. [DOI] [PubMed] [Google Scholar]
  11. Gore-Langton R. E., Dorrington J. H. FSH induction of aromatase in cultured rat granulosa cells measured by a radiometric assay. Mol Cell Endocrinol. 1981 May;22(2):135–151. doi: 10.1016/0303-7207(81)90087-3. [DOI] [PubMed] [Google Scholar]
  12. Graves P. E., Salhanick H. A. Stereoselective inhibition of aromatase by enantiomers of aminoglutethimide. Endocrinology. 1979 Jul;105(1):52–57. doi: 10.1210/endo-105-1-52. [DOI] [PubMed] [Google Scholar]
  13. Haley N. J., Hoffmann D. Analysis for nicotine and cotinine in hair to determine cigarette smoker status. Clin Chem. 1985 Oct;31(10):1598–1600. [PubMed] [Google Scholar]
  14. Herning R. I., Jones R. T., Benowitz N. L., Mines A. H. How a cigarette is smoked determines blood nicotine levels. Clin Pharmacol Ther. 1983 Jan;33(1):84–90. doi: 10.1038/clpt.1983.12. [DOI] [PubMed] [Google Scholar]
  15. Ishiyama I., Nagai T., Toshida S. Detection of basic drugs (methamphetamine, antidepressants, and nicotine) from human hair. J Forensic Sci. 1983 Apr;28(2):380–385. [PubMed] [Google Scholar]
  16. Jensen J., Christiansen C., Rødbro P. Cigarette smoking, serum estrogens, and bone loss during hormone-replacement therapy early after menopause. N Engl J Med. 1985 Oct 17;313(16):973–975. doi: 10.1056/NEJM198510173131602. [DOI] [PubMed] [Google Scholar]
  17. Jick H., Porter J. Relation between smoking and age of natural menopause. Report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. Lancet. 1977 Jun 25;1(8026):1354–1355. doi: 10.1016/s0140-6736(77)92562-4. [DOI] [PubMed] [Google Scholar]
  18. Kellis J. T., Jr, Vickery L. E. Inhibition of human estrogen synthetase (aromatase) by flavones. Science. 1984 Sep 7;225(4666):1032–1034. doi: 10.1126/science.6474163. [DOI] [PubMed] [Google Scholar]
  19. Kew R. R., Ghebrehiwet B., Janoff A. Cigarette smoke can activate the alternative pathway of complement in vitro by modifying the third component of complement. J Clin Invest. 1985 Mar;75(3):1000–1007. doi: 10.1172/JCI111760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lesko S. M., Rosenberg L., Kaufman D. W., Helmrich S. P., Miller D. R., Strom B., Schottenfeld D., Rosenshein N. B., Knapp R. C., Lewis J. Cigarette smoking and the risk of endometrial cancer. N Engl J Med. 1985 Sep 5;313(10):593–596. doi: 10.1056/NEJM198509053131001. [DOI] [PubMed] [Google Scholar]
  21. MacMahon B., Trichopoulos D., Cole P., Brown J. Cigarette smoking and urinary estrogens. N Engl J Med. 1982 Oct 21;307(17):1062–1065. doi: 10.1056/NEJM198210213071707. [DOI] [PubMed] [Google Scholar]
  22. McNatty K. P., Smith D. M., Makris A., Osathanondh R., Ryan K. J. 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. 1979 Dec;49(6):851–860. doi: 10.1210/jcem-49-6-851. [DOI] [PubMed] [Google Scholar]
  23. Meldrum D. R., Davidson B. J., Tataryn I. V., Judd H. L. Changes in circulating steroids with aging in postmenopausal women. Obstet Gynecol. 1981 May;57(5):624–628. [PubMed] [Google Scholar]
  24. Mochizuki M., Maruo T., Masuko K., Ohtsu T. Effects of smoking on fetoplacental-maternal system during pregnancy. Am J Obstet Gynecol. 1984 Jun 15;149(4):413–420. doi: 10.1016/0002-9378(84)90156-x. [DOI] [PubMed] [Google Scholar]
  25. Russell M. A., Feyerabend C. Cigarette smoking: a dependence on high-nicotine boli. Drug Metab Rev. 1978;8(1):29–57. doi: 10.3109/03602537808993776. [DOI] [PubMed] [Google Scholar]
  26. Russell M. A., Wilson C., Patel U. A., Feyerabend C., Cole P. V. Plasma nicotine levels after smoking cigarettes with high, medium, and low nicotine yields. Br Med J. 1975 May 24;2(5968):414–416. doi: 10.1136/bmj.2.5968.414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sasson I. M., Haley N. J., Hoffmann D., Wynder E. L., Hellberg D., Nilsson S. Cigarette smoking and neoplasia of the uterine cervix: smoke constituents in cervical mucus. N Engl J Med. 1985 Jan 31;312(5):315–316. doi: 10.1056/nejm198501313120516. [DOI] [PubMed] [Google Scholar]
  28. Willett W., Stampfer M. J., Bain C., Lipnick R., Speizer F. E., Rosner B., Cramer D., Hennekens C. H. Cigarette smoking, relative weight, and menopause. Am J Epidemiol. 1983 Jun;117(6):651–658. doi: 10.1093/oxfordjournals.aje.a113598. [DOI] [PubMed] [Google Scholar]
  29. Williams A. R., Weiss N. S., Ure C. L., Ballard J., Daling J. R. Effect of weight, smoking, and estrogen use on the risk of hip and forearm fractures in postmenopausal women. Obstet Gynecol. 1982 Dec;60(6):695–699. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES