IN-VIVO MURINE STUDIES ON THE BIOCHEMICAL-MECHANISM OF ACETAMINOPHEN CATARACTOGENICITY

C57BL/6 and DBA/2 mice are, respectively, susceptible and resistant bo th to the induction of aryl hydrocarbon hydroxylase (cytochrome P450 1 A1, or CYP1A1) and to the cataractogenicity of acetaminophen, which ma y involve its bioactivation to a toxic reactive intermediate, catalyse d by P450 and (or) prostaglandin H synthase (PHS). Following induction of P450 using beta-naphthoflavone, the cataractogenicity of acetamino phen (400 mg/kg ip) in C57BL/6 mice was reduced by pretreatment with t he P450 inhibitors SKF 525A and metyrapone, the glutathione precursor N-acetylcysteine, the antioxidant vitamin E, and the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (p < 0.05). Acetaminophe n (200 mg/kg) cataractogenicity was enhanced by pretreatment with the glutathione depletor diethyl maleate (DEM) and the gamma-glutamylcyste ine synthetase inhibitor buthionine sulfoximine (BSO) (p < 0.05). No s ignificant effect on acetaminophen cataractogenicity was observed usin g the PHS cyclooxygenase inhibitors aspirin or naproxen, or the glutat hione reductase inhibitor 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Accordingly, acetaminophen cataractogenicity in C57BL/6 mice does not appear to be dependent upon bioactivation by PHS. In DBA/2 mice treat ed with beta-naphthoflavone, a high dose of acetaminophen (750 mg/kg i p) was not cataractogenic, even after pretreatment with DEM, BSO, or B CNU. The resistance of DBA/2 mice to acetaminophen cataractogenesis, d espite concomitant pretreatments with an inducer of P450 and several a gents that interfere with glutathione-dependent detoxifying pathways, suggests differences in this strain involving cytoprotective pathways subsequent to acetaminophen bioactivation and detoxification of the ca taractogenic reactive intermediate. These results indicate that acetam inophen cataractogenicity in C57BL/6 mice results from P450-catalysed bioactivation of acetaminophen to a reactive intermediate, possibly a benzoquinone imine and (or) a free radical, the toxicity of which is r educed by glutathione-dependent reactions.