ROLE OF HUMAN CYTOCHROME-P-450-IIE1 IN THE OXIDATION OF MANY LOW-MOLECULAR-WEIGHT CANCER SUSPECTS
ROLE OF HUMAN CYTOCHROME-P-450-IIE1 IN THE OXIDATION OF MANY LOW-MOLECULAR-WEIGHT CANCER SUSPECTS
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DOI：
10.1021/tx00020a008
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发表时间：
1991-03-01
影响因子：
4.1
通讯作者：
IWASAKI, M
中科院分区：
文献类型：
--
作者：
GUENGERICH, FP;KIM, DH;IWASAKI, M
人细胞色素P-450 IIE 1的作用（P-450 IIE 1）在氧化许多可疑致癌物中的作用通过多种方法进行了检测，包括（1）二乙基二硫代氨基甲酸酯对人肝微粒体中催化活性的选择性抑制，发现二乙基二硫代氨基甲酸酯是P-450 IIE 1的选择性机制灭活剂，（2）不同催化活性的速率彼此之间以及与人肝微粒体中P-450 IIE 1的指示剂氯唑沙宗6-羟基化的相关性，（3）在含有纯化的人P-450 IIE 1的重构系统中的催化活性的证明，（4）兔抗人P-450 IIE 1对人肝微粒体催化活性的免疫抑制作用。 结果共同表明，P-450 IIE 1是苯、苯乙烯、CCl 4、CHCl 3、CH 2Cl 2、CH 3Cl、CH 3CCl 3、1，2-二氯丙烷、二氯乙烷、二溴乙烷、氯乙烯、溴乙烯、丙烯腈、氨基甲酸乙烯酯、氨基甲酸乙酯和三氯乙烯氧化的主要催化剂。 P-450 IIE 1的水平在不同的人之间有很大的差异--氯唑沙宗作为人P-450 IIE 1的非侵入性探针和双硫仑（氧化二乙基二硫代氨基甲酸酯）作为抑制剂的可用性可能有助于识别人P-450 IIE 1作为这些癌症嫌疑人的生物活化和解毒因子的体内意义。 此外，在人类和实验动物中使用二乙基二硫代氨基甲酸酯、双硫仑和乙醇的许多研究可以根据涉及P-450 IIE 1的机制进行解释。
The role of human cytochrome P-450 IIE1 (P-450 IIE1) in the oxidation of a number of suspect carcinogens was examined by using a variety of approaches, including (1) selective inhibition of catalytic activity in human liver microsomes by diethyldithiocarbamate, which was found to be a selective mechanism-based inactivator of P-450 IIE1, (2) correlation of rates of different catalytic activities with each other and with chlorzoxazone 6-hydroxylation, an indicator of P-450 IIE1, in human liver microsomes, (3) demonstration of catalytic activity in reconstituted systems containing purified human P-450 IIE1, and (4) immunoinhibition of catalytic activity in human liver microsomes with rabbit anti-human P-450 IIE1. The results collectively indicate that P-450 IIE1 is a major catalyst of the oxidation of benzene, styrene, CCl4, CHCl3, CH2Cl2, CH3Cl, CH3CCl3, 1,2-dichloropropane, ethylene dichloride, ethylene dibromide, vinyl chloride, vinyl bromide, acrylonitrile, vinyl carbamate, ethyl carbamate, and trichloroethylene. Levels of P-450 IIE1 can vary considerably among individual humans-the availability of chlorzoxazone as a noninvasive probe of human P-450 IIE1 and of disulfiram (oxidized diethyldithiocarbamate) as an inhibitor may facilitate discernment of the in vivo significance of human P-450 IIE1 as a factor in the bioactivation and detoxication of these cancer suspects. Further, many investigations with diethyldithiocarbamate, disulfiram, and ethanol in humans and experimental animals may be interpreted in light of mechanisms involving P-450 IIE1.