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Metabolic evidence for the involvement of enzymatic bioactivation in the cataractogenicity of acetaminophen in genetically susceptible (C57BL6) and resistant (DBA2) murine strains

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Abstract

Acetaminophen has been shown to be cataractogenic in mice and rabbits. C57BL6 and DBA2 mice respectively are genetically susceptible and resistant to the induction of cytochrome P-448 by 3-methylcholanthrene (3-MC). This isoenzyme is thought to bioactivate acetaminophen to a toxic reactive intermediate. These two murine strains also are correspondingly susceptible and resistant to acetaminophen cataractogenesis. To evaluate the potential role of enzymatic bioactivation as a determinant of acetaminophen cataractogenesis, C57BL6 and DBA2 mice were treated with acetaminophen, 300 or 400 mg/kg intraperitoneally (ip), with or without pretreatment 48 hr earlier using 3-MC, 200 mg/kg ip. Lenticular cataracts were evaluated using the unaided eye and a slit lamp, and hepatotoxicity was evaluated by determination of peak plasma concentration of alanine aminotransferase (ALT). Plasma concentrations of acetaminophen and metabolites, particularly the glutathione (GSH)-derived conjugates (cysteine and mercapturic acid) reflecting enzymatic bioactivation, were measured by high-performance liquid chromatography. Cataracts developed only in C57BL6 mice pretreated with 3-MC, occurring in 1 of 5 and 5 of 5 animals treated respectively with 300 and 400 mg/kg of acetaminophen. Comparing these two groups of induced C57BL6 mice, production of the cysteine conjugate of acetaminophen was 2.5-fold higher with the 400 mg/kg dose of acetaminophen (p < 0.05). Compared to their respective dose-matched, noninduced controls, cysteine conjugate production in the 300 and 400 mg/kg dose groups of induced C57BL6 mice respectively was 3-fold and 4-fold higher (p < 0.05). No DBA2 mice developed cataracts. No mercapturic acid conjugate was detectable in the plasma of DBA2 mice, and production of the cysteine conjugate was not altered in this strain by increasing the dose of acetaminophen or by pretreatment with 3-MC. The mean peak plasma concentration of the cysteine conjugate, reflecting acetaminophen bioactivation, was 5-fold higher in animals developing cataracts compared with those without cataracts (p < 0.001). Plasma concentrations of unmetabolized acetaminophen were similar in all groups and unrelated to the development of cataracts. All mice of both strains pretreated with 3-MC showed evidence of hepatotoxicity, indicating a dissociation between hepatotoxic and cataractogenic susceptibility. The dependence of acetaminophen-induced cataracts upon P-448 induction, and the apparent obligatory relation between the elevation of GSH-derived metabolites and the development of cataracts, suggest that enzymatic bioactivation may be a critical determinant of acetaminophen cataractogenesis.

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A preliminary report of this work was presented at the annual meeting of the Association for Research in Vision and Ophthalmology, Sarasota, Florida, May 1987 (Invest. Ophthalmol. Vis. Sci. 1987 28, 282). Supported in part by grants to P.G.W. and P.K.B. from the Medical Research Council of Canada.

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