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Hormonal Regulation of Levels of the Messenger RNA Encoding Hepatic P450 2c (IIC11), a Constitutive Male-Specific Form of Cytochrome P450

Department of Cell Biology, Kaplan Cancer Center, New York University School of Medicine New York, New York 10016
Department of Biological Chemistry and Molecular Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School Boston, Massachusetts 02115

Address requests for reprints to: Dr. Milton Adesnik, Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, New York 10012.

Abstract

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 4.5–5.5 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 16a-hydroxylase to those of intact males. In male rats treated with estradiol valerate, mRNAs for P450 2c and _2u-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. Hypophysectomy 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 _2u-globulin mRNA levels fell to undetectable values after hypophysectomy 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.

FOOTNOTES

This work was supported by Grants GM-30701 (to M.A.) and DK-33765 (to D.J.W.).

^* Present address: Department of Microbiology, Downstate Medical Center, State University of New York, 450 Clarkson Avenue, Brooklyn, New York 11203.

Received for publication October 2, 1989. Revision received November 15, 1989. Accepted for publication November 15, 1989.

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