Female-predominant rat hepatic P-450 forms j (IIE1) and 3 (IIA1) are under hormonal regulatory controls distinct from those of the sex-specific P-450 forms.
Hepatic expression of cytochrome P-450j (alcohol-inducible nitrosamine demethylase; P-450 gene IIE1) and P-450 3 (testosterone 7 alpha-hydroxylase; P-450 gene IIA1) is female predominant in adult rats [female/male greater than or equal to 1.5-2 (P-450j) or 3-4 (P-450 3)]. This sex difference emerges during the postsuckling period, when P-450 3 declines significantly (60-70% decrease) in male, but not female, rats, and P-450j declines in both sexes, but to a lower constitutive level in males than in females. The biochemical factors and regulatory events that control these developmental changes were investigated and found to be distinct from those that regulate expression of the female-specific hepatic enzymes P-450 2d (P-450 gene IIC12) and steroid 5 alpha-reductase. Immunoquantitation of the changes in P-450j and P-450 3 levels in hormonally altered rats established that both P-450s are under gonadal control. However, while androgen and estrogen both suppress P-450j expression, estrogen stimulates and androgen suppresses the expression of P-450 3. Since many of the effects of gonadal hormones on hepatic enzyme levels are mediated by the pituitary, the contribution of pituitary hormones to P-450j and P-450 3 expression was evaluated. Hypophysectomy of adult rats of either sex elevated P-450j to the levels found in immature rats (3- to 5-fold increase). This elevation was largely reversed in both sexes by GH administered either intermittently or continuously, demonstrating that P-450j is under the suppressive control of this pituitary hormone. The regulation of P-450 3 was more complex. Hypophysectomy elevated P-450 3 to prepubertal levels in adult male rats, but had no effect on P-450 3 levels in adult females. In both sexes GH suppressed P-450 3 expression when administered to hypophysectomized rats intermittently, but stimulated P-450 3 expression when infused continuously. Corresponding changes in hepatic microsomal P-450 3-dependent testosterone 7 alpha-hydroxylase and P-450j-dependent aniline hydroxylase activities were observed in response to hypophysectomy and GH replacement, but only after supplementation of microsomal NADPH P-450 reductase [which was 63-77% suppressed by hypophysectomy] with exogenous purified NADPH P-450 reductase. These studies demonstrate that these female-predominant hepatic P-450 enzymes are regulated by different mechanisms, and that both are under hormonal regulatory controls distinct from those that govern expression of the female-specific hepatic enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)
Waxman
D J
DJ
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
Morrissey
J J
JJ
LeBlanc
G A
GA
D000375:Aging; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004963:Estrenes / Q000494:pharmacology; D005260:Female; D013006:Growth Hormone / Q000494:pharmacology; D007016:Hypophysectomy; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000254:growth & development; D008297:Male; D015741:Metribolone; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009919:Orchiectomy; D010052:Ovariectomy; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D012016:Reference Values; D012737:Sex Factors
D004963:Estrenes; D007527:Isoenzymes; D015741:Metribolone; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System