Kwok E S, Eastmond D A
Environmental Toxicology Program, University of California, Riverside 92521, USA.
Chem Res Toxicol. 1997 Jul;10(7):742-9. doi: 10.1021/tx9700331.
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.
邻苯基苯酚（OPP）及其钠盐（SOPP）是人类经常接触的广谱杀菌剂和抗菌剂。已发现高剂量的OPP和SOPP均可导致雄性F344大鼠膀胱致癌，并且代谢物苯氢醌（PHQ）被认为在这些化合物的致癌性中起关键作用。还表明，治疗动物中的肿瘤形成受尿液pH值的显著影响。为了进一步深入了解OPP致癌机制，我们研究了在OPP和SOPP处理大鼠尿液中常见的pH范围内PHQ的自氧化作用。在所研究的pH范围（6.3 - 7.6）内，观察到PHQ氧化速率与pH之间呈曲线关系。PHQ自氧化过程中形成了苯基苯醌（PBQ），生成产率为0.92±0.02。此外，还研究了PBQ和氧气浓度对PHQ自氧化以及PBQ非酶促转化为PHQ的影响。我们的数据表明，PHQ产生反应性代谢物涉及一个pH无关（即氧依赖）途径和一个pH依赖途径，并且发现PBQ的存在会增强pH依赖的PHQ自氧化速率。已制定了一个反应机制来解释所观察到的实验数据，其中PHQ半醌的电离被确定为pH依赖途径中产生反应性物种的关键步骤。通过将OPP动物致癌性研究数据与所提出的反应途径相结合，观察到所提出的反应性物种形成与膀胱病变之间具有良好的相关性。这些结果表明，尿液中游离PHQ代谢物的pH依赖自氧化可能是导致大鼠膀胱中观察到的OPP和SOPP致癌作用的原因。
