|Budget Amount *help
¥3,200,000 (Direct Cost : ¥3,200,000)
Fiscal Year 1999 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1998 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1997 : ¥1,600,000 (Direct Cost : ¥1,600,000)
The purpose of the present study was to clarify the role that 3-methylsulfonyl (3-MeSOィイD22ィエD2) metabolites play in altering the hepatic microsomal drug-metabolizing enzyme system by polychlorinated biphenyl (PCB) congeners. Additionally we have investigated the biological activities and toxicological effects of the 3- and 4-MeSOィイD22ィエD2 metabolites of PCB congeners. We synthesized eleven 3-MeSOィイD22ィエD2 and two 4-MeSOィイD22ィエD2 metabolites of PCB congeners (which were reported to remain in human milk, liver and adipose tissue and the tissues of several mammalian species) and their two structurally similar 3-MeSOィイD22ィエD2-PCBs.
1. The results of present study show that the structure-CYP2B1/2 induction relationship exists for the 3-MeSOィイD22ィエD2 derivatives studied.
2. The results show that 3-MeSOィイD22ィエD2-2,2',4',5,5'-pentachlorobiphenyl (3-MeSOィイD22ィエD2-2,2',4',5,5'-pentaCB) is a potent phenobarbital (PB)-type inducer of hepatic drug-metabolizing enzymes in both male and female rats, a
nd that there is no sex difference in the induction of the drug-metabolizing enzyme activities by treatment with 3-MeSOィイD22ィエD2-2,2',4',5,5'-pentaCB. The 4-MeSOィイD22ィエD2 isomer had little effect in both male and female rats.
3. The results provide the evidence that the induction of some drug-metabolizing enzymes and δ-aminolevulinic acid synthetase by 2,2',4,5,5'-pentaCB is due not to the action of 2,2',4,5,5'-pentaCB itself but to its 3-methylsulfonyl metabolite, 3-MeSOィイD22ィエD2-2,2',4',5,5'-pentaCB.
4. The results show that 3- and 4-MeSOィイD22ィエD2 metabolites of the PCB congeners tested inhibit gap junction intercellular communication at about the same potency as their parental compounds. Since inhibition of cell communication is often observed after treatment with many tumor promoters, the results suggest that the metabolites may also act as tumor promoters.
5. The results show that the nine tested 3- and 4-MeSOィイD22ィエD2 metabolites of tetra-, penta- and hexaCBs reduce throid hormone levels in rats, suggesting that the metabolites may act as endocrine-disrupters.
6. The results indicate that increase in the hepatic thyroxine (TィイD24ィエD2 glucuronidation after the administration of the seven 3-MeSOィイD22ィエD2-PCBs and 4-MeSOィイD22ィエD2-2,2',4',5,5'-pentaCB possibly because of the induction of both UGT1A1 and UGT1A6 caused the reduction of serum TィイD24ィエD2 levels. Less