Effects of pH on nonenzymatic oxidation of phenylhydroquinone: potential role in urinary bladder carcinogenesis induced by o-phenylphenol in Fischer 344 rats.
o-Phenylphenol (OPP) and its sodium salt (SOPP) are broad spectrum fungicides and antibacterials to which humans are frequently exposed. Both OPP and SOPP have been found to cause cancer in the urinary bladder of male F344 rats at high doses, and the metabolite phenylhydroquinone (PHQ) is believed to play a key role in the carcinogenicity of these compounds. Tumor formation in the treated animals has also been shown to be significantly influenced by urinary pH. To provide additional insights into the mechanisms of OPP carcinogenesis, we have investigated the autoxidation of PHQ over the pH range commonly found in the urine of OPP- and SOPP-treated rats. Over the pH range studied (6.3-7.6), a curvilinear relationship between rate of PHQ oxidation and pH was observed. Phenylbenzoquinone (PBQ) was formed during the autoxidation of PHQ, with a formation yield of 0.92 +/- 0.02. In addition, the effects of PBQ and oxygen concentrations on PHQ autoxidation and the nonenzymatic conversion of PBQ to PHQ were also studied. Our data indicate that the production of reactive metabolites from PHQ involves a pH-independent (i.e., oxygen-dependent) and a pH-dependent pathway and that the rate of pH-dependent PHQ autoxidation was found to be enhanced by the presence of PBQ. A reaction mechanism has been formulated to explain the experimental data observed, with ionization of PHQ semiquinone being identified as a key step in reactive species production for the pH-dependent pathway. By combining data from OPP animal carcinogenicity studies with the proposed reaction pathway, a good correlation between the proposed formation of reactive species and bladder lesions was observed. These results indicate that the pH-dependent autoxidation of free PHQ metabolite in the urine may potentially be responsible for the tumorigenic effects of OPP and SOPP observed in the rat bladder.
Kwok
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ES
Environmental Toxicology Program, University of California, Riverside 92521, USA.
Eastmond
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DA
D000818:Animals; D016227:Benzoquinones / Q000378:metabolism; D001713:Biphenyl Compounds / Q000378:metabolism* / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D005609:Free Radicals / Q000378:metabolism; D005659:Fungicides, Industrial / Q000633:toxicity*; D006863:Hydrogen-Ion Concentration; D006873:Hydroquinones / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000378:metabolism*
D016227:Benzoquinones; D001713:Biphenyl Compounds; D002273:Carcinogens; D005609:Free Radicals; D005659:Fungicides, Industrial; D006873:Hydroquinones; D017382:Reactive Oxygen Species; C029322:phenylbenzoquinone; C004369:2-phenylphenol; C066330:phenylhydroquinone