Enalapril hepatotoxicity in the rat. Effects of modulators of cytochrome P450 and glutathione.
The effects of modulators of cytochrome P450 and reduced glutathione (GSH) on the hepatotoxicity of enalapril maleate (EN) were investigated in Fischer 344 rats. Twenty-four hours following the administration of EN (1.5 to 1.8 g/kg), increased serum transaminases (ALT and AST) and hepatic necrosis were observed. Pretreatment of the animals with pregnenolone-16 alpha-carbonitrile, a selective inducer of the cytochrome P450IIIA gene subfamily, enhanced EN-induced hepatotoxicity, whereas pretreatment with the cytochrome P450 inhibitor, cobalt protoporphyrin, reduced the liver injury. Depletion of hepatic non-protein sulfhydryls (NPSHs), an indicator of GSH, by combined treatment with buthionine sulfoximine (BSO) and diethyl maleate (DEM) produced marked elevations in serum transaminases by 6 hr after EN treatment. Administered on its own, EN decreased hepatic NPSH content and when combined with the BSO/DEM pretreatment, the liver was nearly completely devoid of NPSHs. Protection from EN-induced hepatotoxicity was observed in animals administered L-2-oxothiazolidine-4-carboxylic acid, a cysteine precursor. Together, these observations suggest the involvement of cytochrome P450 in EN bioactivation and GSH in detoxification. The results corroborate previous in vitro observations pertaining to the mechanism of EN-induced cytotoxicity towards primary cultures of rat hepatocytes. Although the doses of EN used in this study were far in excess of therapeutic doses, under certain circumstances, this metabolism-mediated toxicologic mechanism could form the basis for idiosyncratic liver injury in patients receiving EN therapy.
Jurima-Romet
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Toxicology Section, Health and Welfare Canada, Ottawa.
Huang
H S
HS
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000493:pharmacokinetics / Q000633:toxicity*; D004790:Enzyme Induction; D005978:Glutathione / Q000378:metabolism*; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009336:Necrosis; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid; D051381:Rats; D011916:Rats, Inbred F344; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines
D015415:Biomarkers; D065607:Cytochrome P-450 Enzyme Inhibitors; D011524:Protoporphyrins; D013438:Sulfhydryl Compounds; D013844:Thiazoles; D053778:Thiazolidines; D011285:Pregnenolone Carbonitrile; C007095:cobaltiprotoporphyrin; D004656:Enalapril; D003577:Cytochrome P-450 Enzyme System; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid