Kolachana P, Subrahmanyam V V, Eastmond D A, Smith M T
Department of Biomedical and Environmental Health Sciences, School of Public Health, University of California, Berkeley 94720.
Carcinogenesis. 1991 Jan;12(1):145-9. doi: 10.1093/carcin/12.1.145.
o-Phenylphenol (OPP) and its sodium salt sodium ortho-phenylphenate (NaOPP) are broad spectrum fungicides and antibacterial agents. Both are urinary bladder and renal carcinogens in the Fischer 344 rat. OPP is converted by mixed-function oxidases in the liver to phenylhydroquinone (PHQ). Since appreciable amounts of prostaglandin (H) synthase (PGS) are found in rat bladder and kidney-medullary papilla, the target sites of OPP- and NaOPP-induced tumors, we hypothesized that a secondary PGS-mediated activation of PHQ to phenylbenzoquinone (PBQ) may occur in the bladder and kidney. We have studied the metabolism of PHQ by PGS in the presence of arachidonic acid and hydrogen peroxide as co-factors. These studies showed that PHQ is indeed metabolized to a product having identical spectral and electrochemical properties to PBQ. The disappearance of PHQ with time was stoichiometric to the formation of PBQ. Less than 10% of PHQ was converted to PBQ in the absence of enzyme, indicating that auto-oxidation may play only a minor role in the conversion of PHQ to PBQ. Similar results were obtained when PGS was replaced with either myeloperoxidase or horseradish peroxidase and hydrogen peroxide as co-factor. These studies suggest that the peroxidative metabolism of PHQ by PGS to the reactive PBQ could play an important role in OPP-induced urinary bladder and kidney carcinogenesis in rats.
邻苯基苯酚（OPP）及其钠盐邻苯基苯酚钠（NaOPP）是广谱杀菌剂和抗菌剂。二者在Fischer 344大鼠中均为膀胱和肾脏致癌物。OPP在肝脏中由混合功能氧化酶转化为苯基氢醌（PHQ）。由于在大鼠膀胱和肾髓质乳头（OPP和NaOPP诱导肿瘤的靶位点）中发现了相当数量的前列腺素（H）合酶（PGS），我们推测在膀胱和肾脏中可能会发生由PGS介导的PHQ二级活化生成苯醌（PBQ）的过程。我们研究了在花生四烯酸和过氧化氢作为辅助因子存在的情况下，PGS对PHQ的代谢情况。这些研究表明，PHQ确实被代谢为一种具有与PBQ相同光谱和电化学性质的产物。PHQ随时间的消失与PBQ的形成呈化学计量关系。在没有酶的情况下，不到10%的PHQ转化为PBQ，这表明自动氧化在PHQ转化为PBQ的过程中可能只起次要作用。当用髓过氧化物酶或辣根过氧化物酶替代PGS并以过氧化氢作为辅助因子时，也获得了类似的结果。这些研究表明，PGS将PHQ过氧化代谢为活性PBQ可能在大鼠OPP诱导的膀胱癌和肾癌发生过程中起重要作用。
