Modeling the formation and reactions of benzene metabolites
Modeling the formation and reactions of benzene metabolites
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DOI：
10.1016/j.cbi.2010.01.001
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发表时间：
2010-03-19
影响因子：
5.1
通讯作者：
Sadeghi, Majid M.
中科院分区：
文献类型：
--
作者：
Golding, Bernard T.;Barnes, Martine L.;Sadeghi, Majid M.
一个或多个穆康醛异构体是苯代谢的推定产物。由于多聚甲醛是高活性的双烯类化合物，具有潜在的致突变性，因此它们可能与苯的致癌作用有关。仲醛可能是通过细胞色素P450单加氧酶作用于苯氧化物-奥西平而得到的，苯氧化物-奥西平是苯的既定代谢物。在-78℃的丙酮或-40℃的乙腈中，用单电子氧化剂硝酸铈(IV)硝酸铵(CaN)或三(1，10-邻菲咯啉)六氟磷酸铁(III)氧化苯氧化物-奥西平得到(E，Z)-邻苯二甲醛，经H-1核磁共振分析为单一的非对映异构体。甲苯-1，2-氧化物/2-甲氧基沙平与CaN反应得到(2E，4Z)-6-氧代-2，4-二烯醛。同样，CaN作用于1，6-二甲基苯氧基-2，7-二甲基氧丙烷，得到(3Z，5E)-八-3，5-二烯-2，7-二酮。在体内，苯氧化物-奥塞平可被细胞色素P450单加氧酶氧化生成(E，Z)-邻苯二甲醛。这些观察结果可能与苯氧基-奥西平和其他芳烃氧-氧基平的毒理学有关，因为我们以前已经证明，(E，Z)-二甲醛类似于(Z，Z)-二甲醛，提供了与DNA碱腺嘌呤和鸟嘌呤的外环氨基的吡咯加合物。与它们可能的毒理学意义无关，所描述的实验提供了制备(E，Z)-邻苯二甲醛及其同系物的有用路线。还描述了捕获和分析反应性苯代谢物的方法，例如使用Diels-Alder反应与亲双烯的4-苯基-1，2，4-三唑啉-3，5-二酮捕获芳烃氧化物，并与二烯-1，3-二苯基异苯并呋喃捕获enals。(C)2010爱思唯尔爱尔兰有限公司。保留所有权利。
One or more of the muconaldehyde isomers is a putative product of benzene metabolism. As muconaldehydes are highly reactive dienals and potentially mutagenic they might be relevant to the carcinogenicity of benzene. Muconaldehydes may be derived through the action of a cytochrome P450 monooxygenase on benzene oxide-oxepin, which are established metabolites of benzene. Oxidation of benzene oxide-oxepin either by the one-electron oxidant cerium(IV) ammonium nitrate (CAN) or by iron(III) tris(1,10-phenanthroline) hexafluorophosphate in acetone at -78 degrees C or acetonitrile at -40 degrees C gave (E,Z)-muconaldehyde, which was a single diastereoisomer according to analysis by H-1 NMR spectroscopy. Reaction of toluene-1,2-oxide/2-methyloxepin with CAN gave (2E,4Z)-6-oxo-hepta-2,4-dienal. Similarly, the action of CAN on 1,6-dimethylbenzene oxide-2,7-dimethyloxepin gave (3Z,5E)-octa-3,5-diene-2,7-dione. In vivo, benzene oxide-oxepin could suffer one-electron oxidation by cytochrome P450 mono-oxygenase giving (E,Z)-muconaldehyde. The observations presented may be relevant to the toxicology of benzene oxide-oxepin and other arene oxide-oxepins as we have previously shown that (E,Z)-muconaldehyde, analogously to (Z,Z)-muconaldehyde, affords pyrrole adducts with the exocyclic amino groups of the DNA bases adenine and guanine. Independent of their possible toxicological significance, the experiments described provide preparatively useful routes to (E,Z)-muconaldehyde and its congeners. Methods are also described for the trapping and analysis of reactive benzene metabolites, e.g. using the Diels-Alder reaction with the dienophile 4-phenyl-1,2,4-triazoline-3,5-dione to trap arene oxides and with the diene 1,3-diphenylisobenzofuran to trap enals. (C) 2010 Elsevier Ireland Ltd. All rights reserved.