Growth hormone-dependent and -independent regulation of cytochrome P-450 isozyme expression in streptozotocin-diabetic rats.
The sexually dimorphic GH secretory pattern is thought to be the major factor regulating constitutive expression of hepatic P450IIC11 (P-450h) and P450IIC12 (P-450i). In this study we investigated whether factors other than the diabetes-induced decrease in GH secretion contribute to alterations in P-450 isozyme expression in streptozotocin (STZ)-diabetic rats. In male rats, hepatic P-450h apoprotein and mRNA decreased to 13% and 24% of control male levels, respectively, within 14 days of STZ injection. STZ-diabetes had little effect on expression of P-450i in females. Treatment of diabetic male rats with GH did not reverse the suppression of P-450h. STZ treatment also suppressed P-450h expression in GH-treated hypophysectomized (Hx) male rats, but incompletely. Thus, GH can partially reverse diabetic suppression of P-450h. However, in Hx male rats without GH supplementation, STZ treatment suppressed P-450h apoprotein and mRNA expression to 16% and 6% of nondiabetic Hx male levels, respectively, demonstrating the existence of GH-independent regulation of P-450h expression. In Hx female rats, P-450h apoprotein levels were 40% of those in intact control males and were not significantly decreased by STZ. Concomitantly, STZ produced a greater decrease in serum insulin levels and a greater increase in serum glucagon in Hx male rats than in Hx females. The results provide evidence for the existence of STZ-sensitive GH-independent expression of P-450h and further document the gender differences in STZ sensitivity.
Donahue
B S
BS
Department of Pharmacology, Emory University, Atlanta, Georgia 30322.
Skottner-Lundin
A
A
Morgan
E T
ET
D000510:Alpha-Globulins / Q000235:genetics; D000818:Animals; D001059:Apoproteins / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D013006:Growth Hormone / Q000494:pharmacology*; D007016:Hypophysectomy; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains
D000510:Alpha-Globulins; D001059:Apoproteins; D001786:Blood Glucose; D007328:Insulin; D007527:Isoenzymes; D008055:Lipids; C013803:alpha 2u globulin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System