Cotinine and nicotine inhibit human fetal adrenal 11 beta-hydroxylase.
The effects of nicotine and cotinine on fetal adrenal 11 beta- and 21-hydroxylase were examined using enzymatic and spectral techniques. The addition of nicotine or cotinine to preparations of adrenal mitochondria yielded a type II cytochrome P-450 binding spectrum. The apparent spectral dissociation constants (Ks) for nicotine and cotinine binding to mitochondrial cytochrome P-450 were 20 and 19 microM, respectively. The addition of nicotine to preparations of adrenal microsomes yielded a type II cytochrome P-450 binding spectrum, with an apparent Ks of 70 microM. Adrenal mitochondrial 11 beta-hydroxylase was assayed by measuring the conversion of deoxycorticosterone to corticosterone. Nicotine and cotinine competitively inhibited 11 beta-hydroxylase, with apparent Michaelis-Menten inhibition constants (Ki) of 9.9 and 9.0 microM, respectively. Nicotine competitively inhibited microsomal 21-hydroxylase, with an apparent Ki of 110 microM. Cotinine, in concentrations as high as 1 mM, did not inhibit 21-hydroxylase. These results suggest that nicotine and cotinine inhibit 11 beta-hydroxylase by binding to the heme iron of the cytochrome P-450 component of this enzyme system. Inhibition of 11 beta-hydroxylase could contribute to the altered pattern of steroidogenesis observed in smokers.
Barbieri
R L
RL
Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts.
Friedman
A J
AJ
Osathanondh
R
R
D000311:Adrenal Glands / Q000196:embryology* / Q000201:enzymology; D003367:Cotinine / Q000494:pharmacology*; D005260:Female; D005333:Fetus; D006801:Humans; D007700:Kinetics; D009538:Nicotine / Q000494:pharmacology*; D011247:Pregnancy; D011760:Pyrrolidinones / Q000494:pharmacology*; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors*; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*
D011760:Pyrrolidinones; D009538:Nicotine; D013250:Steroid Hydroxylases; D013252:Steroid 11-beta-Hydroxylase; D003367:Cotinine