Metabolic activation of 1-naphthol by rat liver microsomes to 1,4-naphthoquinone and covalent binding species |
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Authors: | M D Doherty G M Cohen |
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Institution: | Toxicology Unit, Department of Pharmacology, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, U.K. |
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Abstract: | 1-Naphthol was metabolized by rat liver microsomes, in the presence of an NADPH-generating system, both to methanol-soluble metabolites including 1,4-naphthoquinone and an uncharacterized product(s) (X) and also to covalently bound products. NADH was much less effective as an electron donor than NADPH. Metyrapone, SKF 525-A and carbon monoxide all inhibited the metabolism of 1-naphthol to 1,4-naphthoquinone and to covalently bound products suggesting the involvement of cytochrome P-450 in at least one step in the metabolic activation of 1-naphthol to reactive products. Ethylene diamine, which reacts selectively with 1,2-naphthoquinone but not 1,4-naphthoquinone, did not affect the covalent binding whereas glutathione, which reacts with both naphthoquinones, caused an almost total inhibition of covalent binding. These and other results suggested that 1,4-naphthoquinone, or a metabolite derived from it, was responsible for most of the covalent binding observed and that little if any of the binding was due to 1,2-naphthoquinone. |
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