Cotinine and Nicotine Inhibit Human Fetal Adrenal 1lβ-Hydroxylase

Publisher Website
Google Scholar
Abstract
The effects of nicotine and cotinine of 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 .mu.M, 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 .mu.M. 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 .mu.M, respectively. Nicotine competitively inhibited microsomal 21-hydroxylase, with an apparent Ki of 110 .mu.M. 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.