Ushiyama K, Nagai F, Nakagawa A, Kano I
Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Japan.
Carcinogenesis. 1992 Aug;13(8):1469-73. doi: 10.1093/carcin/13.8.1469.
[U-14C]o-Phenylphenol (OPP) was found to bind covalently to calf thymus DNA during a 60 min incubation in the presence of microsomes, but not in their absence, indicating that metabolic conversion of the parent compound, OPP, to an activated form is essential. Postlabeling analysis with bladder DNA of rats fed a diet containing 2% OPP for 13 weeks revealed one major adduct on TLC. In an in vitro postlabeling experiment with calf thymus DNA, both of the major metabolites of OPP, phenylhydroquinone (PHQ) and phenylbenzoquinone (PBQ), formed adducts, but no adducts were observed with OPP. The chemical structure responsible for adduct formation is thought to be the PHQ semiquinone radical intermediate formed during interconversion between PHQ and PBQ. When the oligonucleotides, pd(A)12-18, pd(C)12-18, pd(G)12-18 and pd(T)12-18, were used in vitro, only pd(G)12-18 gave TLC-detectable adducts on treatment with PHQ and PBQ. The covalent binding appears to be rather specific to guanine residues. These results suggest that covalent binding of the OPP metabolite is one of the underlying events in OPP-induced carcinogenesis in rats.
在微粒体存在的情况下孵育60分钟后，发现[U-14C]邻苯基苯酚（OPP）与小牛胸腺DNA发生共价结合，但在无微粒体的情况下则不会，这表明母体化合物OPP代谢转化为活化形式是必不可少的。对喂食含2%OPP饮食13周的大鼠膀胱DNA进行标记后分析，在薄层层析（TLC）上显示出一种主要加合物。在一项用小牛胸腺DNA进行的体外标记后实验中，OPP的两种主要代谢物，苯氢醌（PHQ）和苯醌（PBQ），都形成了加合物，但未观察到OPP形成加合物。据认为，形成加合物的化学结构是在PHQ和PBQ相互转化过程中形成的PHQ半醌自由基中间体。当在体外使用寡核苷酸pd(A)12 - 18、pd(C)12 - 18、pd(G)12 - 18和pd(T)12 - 18时，只有pd(G)12 - 18在用PHQ和PBQ处理后产生了TLC可检测的加合物。共价结合似乎对鸟嘌呤残基具有相当的特异性。这些结果表明，OPP代谢物的共价结合是大鼠中OPP诱导致癌作用的潜在事件之一。
