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HUMAN CYTOCHROME P450 ISOZYMES RESPONSIBLE FOR THE METABOLISM OF ORGANIC SOLVENTS AND THEIR ROLES IN THE TOXICITY

负责有机溶剂代谢的人细胞色素 P450 同工酶及其在毒性中的作用

基本信息

批准号：
03454202
负责人：
MURAYAMA Ninzo
金额：
$ 3.58万
依托单位：
SHINSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1993
项目状态：
已结题

项目摘要

1. Metabolisms of organic solvents by cDNA-expressed human hepatic and pulmonary cytochrome P450 were investigated. CYP2B6 was the most effective for the metabolism of toluene, ethlbenzene and stirene, followed by CYP2F1, CYP2E1, CYP1A2, CYP2C8 and CYP4B1, in decreasing order. CYP3A3, CYP3A4 and CYP3A5 showed a little activity for the metabolism, but CYP2A6, CYP2A9 and CYP2D6 did not. On the other hand, CYP2E1 was the most active for the metabolism of benzene and phenol. Although CYP1A2, CYP2B6, CYP2C8 and CYP2F1 were also responsible for the metabolism, the catalytic activity was significantly smaller than that of CYP2E1. CYP1A2 was expressed in human bone marrow, but CYP2E1 could not be seen, suggesting that CYP1A2, not CYP2E1, plays an important role in benzene-induced hematotoxicity. 2.Structure of CYP2B1 cDNA and activity for the metabolism of toluene was investigated. Introduction of 58Phe in place of Leu58 catalysed the formation of benzylalcohol (BA) by 60% of that of CYP2B1, whereas lost the catalitic activity for the formation of o- and p-cresol. The introduction of Phe114 in place of Ile114 catalyzed the formation of all toluene metabolites less than 50% of that by CYP2B1. The introduction of Val282 in place of Glu282 did not influence the activity for the formation of all toluene metabolites. These results suggest the importance of 58Leu of CYP2B1 cDNA in the formation of toluene ring products. 3.Many organic solvents were metabolized in not only human liver but also in lungs.However, the catalitic activity in the latter was only a few percentage of that in the former. Smoking enhanced the activity for the formation of o-cresol from toluene in liver, and of stirene glycol from stirene in lungs. Drinking habit, however, did not influence the metabolism of organic solvents. The metabolic pattern of toluene in human lungs was different from that in liver : the ratio of o- and p-cresol to total metabolites was less than 10% in liver, whereas the ratio o- an

1.研究了人肝、肺细胞色素P450对有机溶剂的代谢。对甲苯、乙苯和苯乙烯的代谢影响最大的是CYP2B6，其次是CYP2F1、CYP2E1、CYP1A2、CYP2C8和CYP4B1。细胞色素P450 3A3、细胞色素P3A4和细胞色素P3A5具有一定的代谢活性，而细胞色素P450 2A6、细胞色素P450 A9和细胞色素P450 D6没有代谢活性。另一方面，对苯和苯酚的代谢活性最强的是CYP2E1。虽然细胞色素P1A2、细胞色素P450_2B6、细胞色素P450_2C8和细胞色素P450_2F1也参与代谢，但催化活性明显低于细胞色素P450_2E_1。人骨髓中有细胞色素P1A2的表达，但未见细胞色素P4502的表达，提示在苯的血液毒性中起重要作用的是细胞色素P1A2，而不是细胞色素P4502。2.研究了细胞色素P450_2B_1基因的结构和对甲苯的代谢活性。引入58Phe取代Leu58，对苯甲醇(BA)的生成催化活性是CYP2B1的60%，而对邻甲酚和对甲酚的生成则失去催化活性。Phe114取代Ile114的引入催化了所有甲苯代谢物的生成，其催化生成的甲苯代谢物不到CYP2B1的50%。引入Val282取代Glu282并不影响所有甲苯代谢物的形成活性。这些结果提示，CYP2B1基因58Leu在甲苯环产物的形成中具有重要作用。3.许多有机溶剂不仅在人的肝脏中代谢，而且在肺中也有代谢，但后者的催化活性仅为前者的几个百分点。吸烟可增强肝脏中甲苯生成邻甲酚的活性和肺中二茂铁乙二醇化的活性。然而，饮酒习惯并不影响有机溶剂的代谢。甲苯在人肺和肝脏中的代谢模式不同：在肝脏中，邻甲酚和对甲酚占总代谢物的比例小于10%，而在肝脏中，邻甲酚和对甲酚占总代谢物的比例较低。