人白细胞髓过氧化物酶代谢活化致癌物4－氨基联苯

本文研究人白细胞髓过氧化物酶（ＭＰＯ）体外代谢芳胺类致癌物４－氨基联苯（４－ＡＢＰ〕在Ｈ２Ｏ２存在下，ＭＰＯ代谢活化４－ＡＢＰ生成二种可与ＤＮＡ共价结合的代谢产物。高效液相色谱和质谱分析表明。在没有ＤＮＡ存在时４－ＡＢＰ的主要代谢产物是偶氮二联苯。抗坏血酸和谷胱甘肽显著抑制活化的４－ＡＢＰ与ＤＮＡ结合。而且可将活化产物还原成４－ＡＢＰ．这些结果结合质谱资料提示活性中间产物可能是４－ＡＢＰ自由基。３２Ｐ－后标记实验证实ＤＮＡ加合物形成，用此种方法检测出８个４－ＡＢＰ－ＤＮＡ加合物。并表明ＭＰＯ介导产生的４－ＡＢＰ－ＤＮＡ加合物与细胞色素Ｐ４５０代谢产物Ｎ－羟基－４－ＡＢＰ和ＤＮＡ反应产生的加合物性质不同．这些结果提示。ＭＰＯ代谢活化途径可能在４－ＡＢＰ诱发肝外组织肿瘤过程中起一定的作用．

Metabolic activation of carcinogen 4-aminobiphenyl byhuman neutrophil myeloperoxidase

The in vitro metabolic activation ofcarcinogenic arylamine 4-aminobiphenyl(4-ABP) bymyeloperoxidase (MPO) from human neutrophils wasinvestigated. In the presence of hydrogen peroxide,4-ABP was metabolized by MPO to form twometabolites which covalently bound to DNA. High per-formance liquid chromatography and massspectrometry analysis showed that in the absence ofDNA the major metabolite of 4-ABP was azobis(biphenyl). Both ascorbic acid and glutathionesignificantly inhibited covalent binding of 4-ABPmetabolites to DNA, and reduced the metabolites backto 4-ABP in the incubation mixture without DNA.Based on these data and mass spectrum of the majorproduct, the active intermediate was suggested to be4-ABP radical. The formation of 4-ABP-DNAadducts was confirined by 32P-postlabelling method.Eight spots of 4-ABP-DNA adducts were detectedand the profile of the adducts formed by MPO wasshown to be different from that fornied bv the reactionof DNA with N-hydroxy-4-ABP, the activated spe-cies of 4-ABP by cytochrome P450. The results sug-gest that the metabolic activation of 4-ABP by MPOmay play a role in the extrahepatic carcinogenesis ofthe careinogen.