In:
Canadian Journal of Physiology and Pharmacology, Canadian Science Publishing, Vol. 73, No. 8 ( 1995-08-01), p. 1123-1129
Abstract:
C57BL/6 and DBA/2 mice are, respectively, susceptible and resistant both to the induction of aryl hydrocarbon hydroxylase (cytochrome P450 1A1, or CYP1A1) and to the cataractogenicity of acetaminophen, which may involve its bioactivation to a toxic reactive intermediate, catalysed by P450 and (or) prostaglandin H synthase (PHS). Following induction of P450 using β-naphthoflavone, the cataractogenicity of acetaminophen (400 mg/kg ip) in C57BL/6 mice was reduced by pretreatment with the P450 inhibitors SKF 525A and metyrapone, the glutathione precursor N-acetylcysteine, the antioxidant vitamin E, and the free radical spin trapping agent α-phenyl-N-t-butylnitrone (p 〈 0.05). Acetaminophen (200 mg/kg) cataractogenicity was enhanced by pretreatment with the glutathione depletor diethyl maleate (DEM) and the γ-glutamylcysteine synthetase inhibitor buthionine sulfoximine (BSO) (p 〈 0.05). No significant effect on acetaminophen cataractogenicity was observed using the PHS cyclooxygenase inhibitors aspirin or naproxen, or the glutathione 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 treated with β-naphthoflavone, a high dose of acetaminophen (750 mg/kg ip) was not cataractogenic, even after pretreatment with DEM, BSO, or BCNU. The resistance of DBA/2 mice to acetaminophen cataractogenesis, despite concomitant pretreatments with an inducer of P450 and several agents that interfere with glutathione-dependent detoxifying pathways, suggests differences in this strain involving cytoprotective pathways subsequent to acetaminophen bioactivation and detoxification of the cataractogenic reactive intermediate. These results indicate that acetaminophen 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 reduced by glutathione-dependent reactions.Key words: cataracts, acetaminophen, genetic susceptibility, acetaminophen cataractogenesis.
Type of Medium:
Online Resource
ISSN:
0008-4212
,
1205-7541
Language:
English
Publisher:
Canadian Science Publishing
Publication Date:
1995
detail.hit.zdb_id:
2004356-9
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