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Immunochemical assessment of the influencing factors on the metabolism of organic solvents

有机溶剂代谢影响因素的免疫化学评估

基本信息

批准号：
02807059
负责人：
NASU Tamie
金额：
$ 1.02万
依托单位：
Shinshu University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1992
项目状态：
已结题

项目摘要

Characterization of cytochrome P450 isozyme responsible for the metabolism of organic solvents and the factors influencing the metabolism were investigated in rats using monoclonal antibody to cytochrome P450. CYP2B1/2, 2E1 and 2C11/6 were involved in toluene side-chain reaction; CYP1A1/2, 2B1/2 and 2C11/6 in o-cresol formation from toluene; CYP1A1/2, 2B1/2, 2E1 and 2C11/6 in p-cresol formation from toluene. These four isozymes were also involved in benzene, styrene and trichloroethylene (TRI) metabolism. CYP2C11/6 was a major isozyme responsible for toluene and styrene metabolism, whereas CYP2E1 in the metabolism of benzene and TRI. In general, CYP2E1 acted the metabolism of organic solvents as a lower Km isozyme than CYP2C11/6. CYP2E1 was induced with ethanol consumption, the intake of low-carbohydrate diet. fasting and diabetic status, whereas decreased with aging and pregnancy. The level of CYP2C11/6 increased with aging, and predominantly expressed in males at adult age. This isozyme, however, decreased with pregnancy and diabetic status. Species differences were found in the metabolism of benzene, toluene, styrene and TRI between rat and mouse. The metabolic rates of benzene and TRI were always higher in adult male mouse than in adult male rat. The rates of toluene and styrene were also higher in mouse than in rat at low substrate concentrations, but the result was reversed at the high concentration. Mouse had much more CYP2E1 than rats, whereas CYP2C11/6 predominantly expressed in rat, suggesting that one reason of species difference in the metabolism of organic solvents between rat and mouse depends on the difference in the distribution of P450 isozymes. CYP2E1 was involved in carbon tetrachloride and chloroform hepatotoxicity at the low level. In conclusion, since cytochrome P450 shows substrate specificity for organic solvents, any hazard from the exposure of organic solvents may depend on the P450 isozyme profile in the target organ.

用抗细胞色素P450单克隆抗体研究了大鼠有机溶剂代谢的细胞色素P450同工酶的特性及其影响因素。CYP 2B 1/2、2 E1和2C 11/6参与甲苯侧链反应; CYP 1A 1/2、2B 1/2和2C 11/6参与甲苯生成邻甲酚; CYP 1A 1/2、2B 1/2、2 E1和2C 11/6参与甲苯生成对甲酚。这四种同工酶还参与苯、苯乙烯和三氯乙烯（TRI）的代谢。CYP 2C 11/6是负责甲苯和苯乙烯代谢的主要同工酶，而CYP 2 E1是负责苯和TRI代谢的主要同工酶。CYP 2 E1作为一种Km值低于CYP 2C 11/6的同工酶参与有机溶剂的代谢。CYP 2 E1的诱导与乙醇的消耗，摄入低碳水化合物的饮食。空腹和糖尿病状态，而随着年龄的增长和怀孕而下降。CYP 2C 11/6的水平随年龄增长而增加，并主要在成年男性中表达。然而，这种同工酶随着妊娠和糖尿病状态而降低。大鼠和小鼠对苯、甲苯、苯乙烯和TRI的代谢存在种属差异。成年雄性小鼠对苯和TRI的代谢率始终高于成年雄性大鼠。在低浓度下，小鼠对甲苯和苯乙烯的反应速率也高于大鼠，但在高浓度下，结果相反。小鼠的CYP 2 E1明显高于大鼠，而CYP 2C 11/6在大鼠中主要表达，提示大鼠和小鼠有机溶剂代谢的种属差异可能与P450同工酶分布的差异有关。CYP 2 E1在低水平上参与了四氯化碳和氯仿的肝毒性。总之，由于细胞色素P450对有机溶剂具有底物特异性，因此有机溶剂暴露的任何危害可能取决于靶器官中的P450同工酶谱。