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

1.研究了cDNA表达的人肝和肺细胞色素P450对有机溶剂的代谢。对甲苯、乙苯和苯乙烯的代谢最有效的是CYP 2B 6，其次是CYP 2F 1、CYP 2 E1、CYP 1A 2、CYP 2C 8和CYP 4 B1，依次递减。CYP 3A 3、CYP 3A 4和CYP 3A 5具有一定的代谢活性，而CYP 2A 6、CYP 2A 9和CYP 2D 6则无代谢活性。另一方面，CYP 2 E1对苯和苯酚的代谢最活跃。虽然CYP 1A 2、CYP 2B 6、CYP 2C 8和CYP 2F 1也负责代谢，但催化活性明显小于CYP 2 E1。CYP 1A 2在人骨髓中有表达，而CYP 2 E1在骨髓中无表达，提示在苯致血液毒性中起重要作用的是CYP 1A 2，而不是CYP 2 E1。2.研究了CYP 2B 1 cDNA的结构和甲苯代谢活性。引入58 Phe代替Leu 58催化苯甲醇（BA）的形成，催化活性为CYP 2B 1的60%，而失去了对邻甲酚和对甲酚的催化活性。引入Phe 114代替Ile 114催化所有甲苯代谢物的形成，其小于CYP 2B 1的50%。引入Val 282代替Glu 282不影响所有甲苯代谢产物形成的活性。这些结果提示CYP 2B 1cDNA的58 Leu在甲苯环产物的形成中起重要作用。3.许多有机溶剂不仅在人肝中代谢，而且在人肺中代谢，但后者的催化活性仅为前者的几个百分点。吸烟增强了肝脏中甲苯生成邻甲酚和肺中苯乙烯生成苯乙烯乙二醇的活性。饮酒习惯对有机溶剂代谢无影响。甲苯在人肺中的代谢模式与在肝中的代谢模式不同：邻甲酚和对甲酚在肝中的比例小于10%，而邻甲酚和对甲酚在肝中的比例小于10%，邻甲酚和对甲酚在肝中的比例小于10%，邻甲酚和对甲酚在肝中的比例小于10%。

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