HORMONAL-REGULATION OF LEVELS OF THE MESSENGER-RNA ENCODING HEPATIC P450 2C (IIC11), A CONSTITUTIVE MALE-SPECIFIC FORM OF CYTOCHROME-P450

A cDNA clone for rat hepatic cytochrome P450 2c (gene product IIC11) was isolated and used to study the sex specificity, expression during development, and hormonal regulation of the mRNA encoding this protein in rat liver. P450 2c mRNA levels were about 16-fold higher in males than in females and were only slightly increased in male rats after administration of phenobarbital, a drug that dramatically raises the levels of mRNAs encoding several other members of the P450 II family. In contrast to the mRNA encoding P450 f (gene product IIC7), which increases gradually over the first 6 weeks of life, P450 2c mRNA showed a dramatic increase at puberty, between 4.S-5.5 weeks of life. The roles of sex steroids and GH in controlling this male-specific, developmentally regulated mRNA were then examined. A dependence on adult androgen was demonstrated by the 2- to 4-fold decrease in P-450 2c mRNA levels after castration of adult male rats and their restoration to normal by administration of the synthetic androgen methyltrienolone. Prolonged treatment (15 days) of ovariectomized female rats with this androgen also increased the levels of P450 2c mRNA and its encoded testosterone 16α-hydrox-ylase to those of intact males. In male rats treated with estradiol valerate, mRNAs for P450 2c and α2u-globulin, a major male-specific hepatic secretory protein that is under complex hormonal control, fell to negligible levels. None of these hormonal perturbations had a detectable effect on the levels of PB-1 (gene product IIC6) mRNA, which is not expressed in a sex-dependent manner. Full expression of P450 2c mRNA depended on the presence of GH pulses, which are known to be in part androgen dependent in adult male rats. Hy-pophysectomy led to a 5- to 10-fold reduction in the levels of P450 2c mRNA, but these returned to near normal when two daily injections of GH were given for 7 days. Levels of PB-1 mRNA were not affected under similar conditions, while α2u-globulin mRNA levels fell to undetectable values after hypophysec-tomy and returned to only 5-10% of the control value after intermittent GH administration. These results demonstrate that the previously reported sex-dependent developmental regulation of P450 2c protein expression is mediated by gonadal and pituitary hormones whose actions are effected by mechanisms that operate primarily, if not exclusively, at a pretranslational step. © 1990 by The Endocrine Society.