Intrinsic sex differences determine expression of growth hormone-regulated female cytochrome P450s.
The masculine profile of cytochrome P450s found in male liver is determined by the episodic secretion of growth hormone characteristic of males. In turn, the female pattern of P450s observed in female rat liver is regulated by the continuous secretion of growth hormone characteristic of the female. In order to determine if intrinsic and possibly permanent sex differences exist in the response of hepatic P450s to growth hormone regulation, we compared the effects of the episodic and continuous growth hormone profiles on the expression of female-dependent isoforms in cultured hepatocytes isolated from both sexes. We observed that female-specific CYP2C12 as well as female-predominant CYP2A1, 3A1, and 2C6 could be induced by growth hormone concentrations equal to as little as 6, 0.6, and 0.06% of the mean circulating hormone profile found in normal females. Irrespective of sex, all four female-dependent isoforms were far more responsive to the continuous growth hormone profile than the episodic pattern. Lastly, female-derived hepatocytes in general responded with strikingly greater induction levels of P450s than male hepatocytes exposed to the same growth hormone profiles. The present findings demonstrate intrinsic, irreversible sex differences in growth hormone-regulated female-dependent P450s.
Thangavel
Chellappagounder
C
Laboratories of Biochemistry, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6048, USA.
Garcia
Martha C
MC
Shapiro
Bernard H
BH
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D013006:Growth Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012727:Sex Characteristics; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics
D012333:RNA, Messenger; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C096409:CYP2C1 protein, Oryctolagus cuniculus; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; C034694:steroid 15-beta-hydroxylase; C029009:steroid hormone 7-alpha-hydroxylase