| Co-Investigator(Kenkyū-buntansha) |
KUROKI Hiroaki Daiichi College of Pharmaceutical Sciences, Professor, 薬学部, 教授 (60258499)
HARAGUCHI Koichi Daiichi College of Pharmaceutical Sciences, Professor, 薬学部, 教授 (00258500)
KANAMARU Tomoyo Nakamura Gakuen University, Department of Food and Nutrition, Instructor, 家政学部, 助手 (50291836)
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| Research Abstract |
The enzyme systems involving in the formation of high persistant PCB metabolites, methylsulfone(MeSO2)-PCBs, were studied using liver microsomes of rats, hamsters and guinea pigs and cDNA-expressed human cytochrome P450 (P450) and flavin containing monooxygenase (FMO). 3- and 4-methylthio (MeS)-2, 5, 3', 4'-tetrachlorobiphenyl (CB70) were used as a substrate. The studies on the effects of their inducers and inhibitors on the S -oxidation of 3- and 4-MeS-CB70 demonstrated that P450 was much more important than FMO in the formation of McS0_2-metabolites in all three animals. The order of the activity for the S-oxidation of MeS-CB70 was guinea pigs ≧ hamsters ≫ rats. On the other hand, a sex difference was observed only in rats, but not in hamsters and guinea pigs. Female rats showed only 20% of the activity of male rats. From these results, it is suggested that three P450 isoforms (CYP1A1, CYP2B1, CYP2C11) in rats, HPB-1(CYP2B) in hamsters and CYP2B18 in guinea pigs could act as an S-oxygcnase of MeS-CB70.Next, the production of MeSO- and MeS0_2-CB70 was investigated using seven cDNA-expressed human P450 and three cDNA-expressed human FMO.
The reaction from MeS to MeSO was catalyzed by CYP1A1, CYP1A2, CYP2B6, CYP2C9*1 and FMO1.Of these enzymes, CYP2B6 and CYP2C9*1 metabolized 3-MeS-CB7O to its MeSO-metabolite more preferentially than 4-MeS-CB70.On the contrary, FMO1 produced 4-MeSO-metabolite from 4-MeS-CB70 exclusively. Moreover, the production of a MeSO2-metabolite was catalyzed by CYP1A1 and CYP2C9*1 but not by other P450 and FMO.
In conclusion, some isofbrms belonging to the P450 subfamily of CYP1A, CYP2B and CYP2C, and a certain FMO, FMO1, involved in liver microsomal S-oxidation of MeS-CB70 in animals including human.
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