title: Comparison of the cytotoxicity of ACE inhibitors and effects of cytochrome P-450 and glutathione modulation in primary rat hepatocyte cultures.
abstract: Hepatotoxicity has been reported with angiotensin-converting enzyme (ACE) inhibitors. The mechanism of liver injury is not known. In the present study, primary rat hepatocytes were used to investigate the cytotoxicity of ACE inhibitors. Captopril, enalapril, fosinopril and quinapril were cytotoxic, as measured by lactate dehydrogenase release at 24 hr, with the rank order of toxicity as quinapril (LC (50) = 0.28 m m ) > fosinopril (LC (50) = 0.4 m m ) > enalapril (LC (50) = 2.0 m m ) > captopril (LC (50) = 20 m m ) . Enalaprilat, the de-esterified metabolite of enalapril, and lisinopril, the lysine analogue of enalaprilat, were not cytotoxic. In vivo pretreatment with pregnenolone-16alpha-carbonitrile (cytochrome P-450 (CYP) 3A induction) enhanced the toxicities of enalapril, fosinopril and quinapril but did not affect the response to captopril. Induction with phenobarbital (CYP2B), beta-naphthoflavone (CYP1A) or ethanol (CYP2E1) did not influence the cytotoxicity of any of the ACE inhibitors. The hypothesis of a CYP3A-mediated bioactivation in the cytotoxicity of enalapril, fosinopril and quinapril was further supported by observations of reduced toxicity in the presence of SKF525-A and troleandomycin. The enhancement of cytotoxicity after pretreatment of the cultures with buthionine sulfoximine suggested a role for glutathione in protection, possibly by detoxifying unknown reactive metabolites.
authors.affiliation: Bureau of Drug Research, Health and Welfare Canada, Banting Research Centre, Tunney's Pasture, Ottawa, Canada K1A 0L2.
authors.forename: M
authors.initials: M
authors.lastname: Jurima-Romet
authors.forename: H S
authors.initials: HS
authors.lastname: Huang