Flesher J W, Horn J, Lehner A F
Department of Pharmacology, Experimental Cancer Research Laboratory, and Graduate Center for Toxicology, Albert B. Chandler Medical Center, University of Kentucky, Lexington, Kentucky, 40536, USA.
Biochem Biophys Res Commun. 1998 Oct 9;251(1):239-43. doi: 10.1006/bbrc.1998.9448.
The role of electrophilic hydroxymethyl sulfate esters in the metabolic activation, DNA-damage, mutagenicity, and complete carcinogenicity of polycyclic aromatic hydrocarbons has been elucidated considerably in recent years. The observations are in agreement with a unified hypothesis which predicts that electrophilic hydroxymethyl sulfate esters and closely related aralkylating agents are major ultimate carcinogenic forms of most, if not all, carcinogenic alkyl-substituted and even unsubstituted carcinogenic polycyclic aromatic hydrocarbons. The common final step in a chain of enzymatic substitution reactions is the formation of an aralkylating agent bearing a good leaving group. Activation of hydroxymethyl derivatives, including 9-hydroxymethylanthracene, to electrophilic mutagens has been shown to be catalyzed by 3'-phosphoadenosine-5'-phosphosulfate-dependent sulfotransferase activity. Recent studies, in a complete carcinogenic model, demonstrate that a number of sulfuric acid ester derivatives are more potent than their hydroxymethyl precursors by repeated subcutaneous injection in female Sprague-Dawley rats. In this paper, these observations have been extended to include 9-sulfooxymethylanthracene as an ultimate electrophilic and carcinogenic form of 9-hydroxymethylanthracene.
近年来,亲电硫酸羟甲酯在多环芳烃的代谢活化、DNA损伤、致突变性和完全致癌性中的作用已得到相当程度的阐明。这些观察结果与一个统一的假说一致,该假说预测亲电硫酸羟甲酯和密切相关的芳烷基化剂是大多数(如果不是全部)致癌烷基取代甚至未取代的致癌多环芳烃的主要最终致癌形式。一系列酶促取代反应的共同最后一步是形成带有良好离去基团的芳烷基化剂。已证明包括9-羟甲基蒽在内的羟甲基衍生物活化为亲电诱变剂是由3'-磷酸腺苷-5'-磷酸硫酸酯依赖性磺基转移酶活性催化的。在一个完全致癌模型中的最新研究表明,通过对雌性Sprague-Dawley大鼠进行重复皮下注射,许多硫酸酯衍生物比其羟甲基前体更具效力。在本文中,这些观察结果已扩展到包括9-磺氧基甲基蒽作为9-羟甲基蒽的最终亲电致癌形式。