Metabolic activation of 1-naphthol and phenol by a simple superoxide-generating system and human leukocytes.
Phenol and 1-naphthol, products of benzene and naphthalene biotransformation, are metabolized during O2- generation by xanthine oxidase/hypoxanthine and phorbol myristate acetate (PMA)-stimulated human neutrophils. The addition of 1-naphthol to xanthine oxidase/hypoxanthine incubations resulted in the formation of 1,4-naphthoquinone (1,4-NQ) whereas phenol addition yielded only small quantities of hydroquinone, catechol and a unidentified reducible product but not 1,4-benzoquinone. This formation of 1,4-NQ was dependent upon hypoxanthine, xanthine oxidase, and 1-naphthol and was inhibited by the addition of superoxide dismutase (SOD) demonstrating that the conversion was O2-mediated. During O2- generation by PMA-stimulated neutrophils, the addition of phenol interfered with luminol-dependent chemiluminescence and resulted in covalent binding of phenol to protein. Protein binding was 80% inhibited by the addition of azide or catalase to the incubations indicating that bioactivation was peroxidase-mediated. In contrast, the addition of 1-naphthol to PMA-stimulated neutrophils interfered with superoxide-dependent cytochrome c reduction as well as luminol-dependent chemiluminescence and also resulted in protein binding. Protein binding was only partially inhibited by azide or catalase. The addition of SOD in combination with catalase resulted in a significantly greater inhibition of binding when compared to that of catalase alone. The results of these experiments indicate that phenol and 1-naphthol are converted to reactive metabolites during superoxide generating conditions but by different mechanisms. The formation of reactive metabolites from phenol was almost exclusively peroxidase-mediated whereas the bioactivation of 1-naphthol could occur by two different mechanisms, a peroxidase-dependent and a direct superoxide-dependent mechanism.
Eastmond
D A
DA
Department of Biomedical and Environmental Health Sciences, School of Public Health, University of California, Berkeley 94720.
French
R C
RC
Ross
D
D
Smith
M T
MT
D016227:Benzoquinones; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000097:blood; D008163:Luminescent Measurements; D009284:Naphthols / Q000493:pharmacokinetics*; D009285:Naphthoquinones / Q000097:blood; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D019800:Phenol; D010636:Phenols / Q000493:pharmacokinetics*; D011809:Quinones / Q000097:blood; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000097:blood*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000097:blood
D016227:Benzoquinones; D001798:Blood Proteins; D007042:Hypoxanthines; D009284:Naphthols; D009285:Naphthoquinones; D010636:Phenols; D011809:Quinones; D013481:Superoxides; C029350:1-naphthol; D019271:Hypoxanthine; D019800:Phenol; C004532:quinone; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D013755:Tetradecanoylphorbol Acetate; C035342:1,4-naphthoquinone