Modulation of carbon tetrachloride hepatotoxicity and xenobiotic-metabolizing enzymes by corticosterone pretreatment, adrenalectomy and sham surgery.
These investigations sought to determine the role of physiological concentrations of natural glucocorticoids in modulating chemical toxicity, and to ascertain if effects on toxicity may be due to alterations of chemical metabolizing enzymes by glucocorticoids. The hepatotoxic response to carbon tetrachloride (CCl4) in adrenalectomized or naive Long Evans rats treated with corticosterone was assessed. Alterations of hepatic cytochrome P-450 concentration, mono-oxygenase activities, NADPH-cytochrome (P-450)c reductase activity, and glutathione S-transferase activity were examined. Adrenalectomy and to a lesser extent sham surgery were protective, but corticosterone administration increased CCl4 hepatotoxicity. Corticosterone administration to adrenalectomized or sham-operated rats reduced the protective effect of these treatments. Correlating with the in vivo response, mono-oxygenase activities decreased after adrenalectomy and sham surgery, but increased with glucocorticoid administration. These studies suggest that basal, stress-associated, and pharmacological concentrations of a natural glucocorticoid can modify chemical toxicity and alter hepatic enzymes important to chemical metabolism.
Lloyd
S A
SA
Molecular Toxicology Group, Oklahoma Medical Research Foundation, Oklahoma City 73104.
Franklin
M R
MR
D000315:Adrenalectomy; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002251:Carbon Tetrachloride / Q000633:toxicity*; D003345:Corticosterone / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D007274:Injections, Intraperitoneal; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D051381:Rats
D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003345:Corticosterone