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

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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