Cytochrome P-450 dependent metabolic activation of 1-naphthol to naphthoquinones and covalent binding species.
1-Naphthol was metabolised by a fully reconstituted cytochrome P-450 system in the presence of NADPH to methanol-soluble and covalently bound products. The formation of 1,4-naphthoquinone, the major methanol-soluble product at early time points, showed an almost total dependence on cytochrome P-450, NADPH-cytochrome P-450 reductase and NADPH, and to a lesser extent on dilauroylphosphatidylcholine. The metabolism was rapid and detectable levels of 1,4-naphthoquinone were formed within 30 sec. 1,4-Naphthoquinone formation was dependent on the concentration of both cytochrome P-450 (0.05-0.04 microM) and 1-naphthol (5-50 microM). Whereas 1,4-naphthoquinone was the major product observed at early time points, additional products were observed after prolonged incubation. In the absence of NADPH and NADPH-cytochrome P-450 reductase, 1-naphthol was metabolised, in a cumene hydroperoxide- and cytochrome P-450-dependent reaction, to 1,2- and 1,4-naphthoquinone and covalently bound products. Glutathione and ethylenediamine inhibited both the NADPH- and cumene hydroperoxide-dependent formation of covalently bound products. These data show that cytochrome P-450 catalyses the activation of 1-naphthol to naphthoquinone metabolites and covalently bound species, the latter most likely being derived from naphthoquinones.
D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology; D001711:Biotransformation; D002250:Carbon Radioisotopes; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D000432:Methanol; D008862:Microsomes, Liver / Q000378:metabolism; D009249:NADP / Q000494:pharmacology; D009284:Naphthols / Q000378:metabolism*; D009285:Naphthoquinones / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D001555:Benzene Derivatives; D002250:Carbon Radioisotopes; D009284:Naphthols; D009285:Naphthoquinones; C029350:1-naphthol; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; C007164:cumene hydroperoxide; D000432:Methanol