| Budget Amount *help |
¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1992: ¥300,000 (Direct Cost: ¥300,000)
Fiscal Year 1991: ¥300,000 (Direct Cost: ¥300,000)
Fiscal Year 1990: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Research Abstract |
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.
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