Regulation of rat hepatic cytochrome P-450: age-dependent expression, hormonal imprinting, and xenobiotic inducibility of sex-specific isoenzymes

Abstract

The influence of age, sex and hormonal status on the expression of 8 rat hepatic cytochrome P-450 (P-450) isoenzymes was evaluated by both catalytic and immunochemical methods. The male specificity of P-450 2c .male./UT-A, the major microsomal steroid 16.alpha.-hydroxylase of uninduced rat liver [Waxman, D.J. (1984)] was shown to reflect its .gtoreq. 30-fold induction at puberty in male but not in female rats. The female specificity of P-450 2d (.female.)/UT-I was shown to reflect its developmental induction in females. P-450 PB-2a/PCN-E was shown to mediate .gtoreq. 85% of microsomal steroid 6.beta.-hydroxylase activity; the male specificity of this P-450 largely reflects its developmental suppression in female rats. Neonatal gonadectomy and hormonal replacement experiments established that neonatal androgen imprints or programs the male rat for developmental induction of P-450 2c (.male.)/UT-A, for maintenance of P-450 PB-2a/PCN-E, and for suppression of P-450 2d (.female.)/UT-I, all of which occur in male rats at puberty. The expressed levels of P-450 isoenzymes PB-1/PB-C, 3/UT-F, PB-4/PB-B, ISF-G, and .beta.NF-B were mostly unaffected by the rats'' age, sex and hormonal status. Studies on the sex specificity of P-450 induction established that the response of these latter 5 isoenzymes to the P-450 inducers phenobarbital, .beta.-napthoflavone, pregnenolone-16.alpha.-carbonitrile, and isosafrole is qualitatively and quantitatively equivalent in females as in males. Although none of these agents effected an induction of P-450 2d (.female.)/UT-I in males or an induction of P-45- 2c (.male.)/UT-A in females, pregnenoline-16.alpha.-carbonitrile administration led to a .gtoreq. 70-fold induction of P-450 PB-2a/PCN-E in female rat liver, thereby abolishing the sex-specific expression of this steroid 6.beta.-hydroxylase P-450. The multiple rat liver P-450 active in foreign compound metabolism are independently regulated by physiological factors and further serve to highlight the complex influences of foreign compound exposure on P-450-catalyzed steroid hormone hydroxylations in rat hepatic tissue.