Pretranslational control by thyroid hormone of rat liver steroid 5 alpha-reductase and comparison to the thyroid dependence of two growth hormone-regulated CYP2C mRNAs.
The sexually differentiated microsomal enzyme steroid 5 alpha-reductase (NADPH: delta 4-3-oxosteroid 5 alpha-oxido-reductase, EC 1.3.99.5) catalyzes the NADPH-dependent conversion of testosterone to 5 alpha-dihydrotestosterone, a more potent androgen. In rat liver, this enzyme is expressed at a 10-fold higher level in adult females as compared to adult males. The pituitary regulation of this enzyme and its mRNA was studied in untreated and hypophysectomized rats and in rats rendered hypothyroid by treatment with the antithyroid drug methimazole. Hepatic 5 alpha-reductase activity was elevated 8-fold, to 85% of adult female levels, in adult male rats given growth hormone by continuous infusion. This same treatment was only partially effective in restoring 5 alpha-reductase in rats depleted of endogenous growth hormone by hypophysectomy, indicating that other pituitary-dependent factors contribute to the elevation observed in the inact animals. Further analysis revealed that thyroxine, but not adrenocorticotropic hormone (ACTH) or chorionic gonadotropin, could elevate 5 alpha-reductase activity and mRNA when given to the hypophysectomized rats and that this effect was enhanced by the presence of growth hormone. This thyroid hormone dependence was confirmed by the decrease in hepatic 5 alpha-reductase expression in hypothyroid rats and by its substantial restoration following thyroxine replacement. Thyroxine also stimulated expression of another female-predominant hepatic mRNA, encoding the steroid 16 alpha-hydroxylase cytochrome P-450f (IIC7), in a manner that was independent of the stimulatory effect of growth hormone on this transcript. In contrast, thyroid hormone did not significantly affect protein or mRNA levels of the growth hormone-stimulated, female-specific steroid sulfate 15 beta-hydroxylase P-450 2d (IIC12). These findings establish that thyroid hormones act at a pretranslational level to modulate the expression of some, but not all, growth hormone-stimulated hepatic mRNAs and demonstrate that both thyroxine and growth hormone can independently contribute to the sex-dependent expression of hepatic enzymes of steroid metabolism.
Ram
P A
PA
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
Waxman
D J
DJ
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D013006:Growth Hormone / Q000494:pharmacology*; D007016:Hypophysectomy; D007037:Hypothyroidism / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008713:Methimazole / Q000494:pharmacology; D005810:Multigene Family; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D012016:Reference Values; D012737:Sex Factors; D039181:Steroid 16-alpha-Hydroxylase; D013974:Thyroxine / Q000097:blood* / Q000494:pharmacology / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects
D012333:RNA, Messenger; D008713:Methimazole; D000324:Adrenocorticotropic Hormone; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; D039181:Steroid 16-alpha-Hydroxylase; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D013974:Thyroxine