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The role of 3-methylsulfony (3-MeSOィイD22ィエD2) metabolites in the induction of hepatic microsomal drug-metabolizing enzymes by PCB congeners, and the toxicological effects of the MeSOィイD22ィエD2 metabolites of PCB congeners

3-甲基磺酰（3-MeSOD22D2）代谢物在PCB同系物诱导肝微粒体药物代谢酶中的作用，以及PCB同系物MeSOD22D2代谢物的毒理学作用

基本信息

批准号：
09680531
负责人：
KATO Yoshihisa
金额：
$ 2.05万
依托单位：
University of Shizuoka
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

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 … More 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

本研究的目的是阐明3-甲基磺酰（3-MeSO γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ）代谢物在多氯联苯（PCB）同源物改变肝微粒体药物代谢酶系统中的作用。此外，我们还研究了多氯联苯同系物的3-和4-MeSO γ - D22 γ - D2代谢物的生物活性和毒理学效应。我们合成了11种3-MeSO D22 D2和2种4-MeSO D22 D2的PCB同系物（据报道存在于人乳、肝脏、脂肪组织和几种哺乳动物组织中）及其两种结构相似的3-MeSO D22 D2- pcbs。本研究结果表明，所研究的3-MeSO γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ。结果表明,3-MeSOィイD22摊位ィエD2-2, 2 ', 4 ', 5 ' -pentachlorobiphenyl (3-MeSOィイD22摊位ィエD2-2, 2 ', 4 ', 5、5 ' -pentaCB)是一种强有力的苯巴比妥(PB)类型的诱导物,在雄性和雌性大鼠肝摘要,a ... 更多的nd,没有性别差异的感应摘要酶活性通过治疗3-MeSOィイD22摊位ィエD2-2, 2 ', 4 ', 5 ' -pentaCB。4-MeSO γ γ γ γ γ对雄性和雌性大鼠均无明显影响。结果提供证据表明,一些摘要的感应和δ-aminolevulinic酸合成酶2,2’,4、5、5 ' -pentaCB是由于不2的作用,2’,4、5、5 ' -pentaCB本身,而是其3-methylsulfonyl代谢物,3-MeSOィイD22摊位ィエD2-2, 2 ', 4 ', 5 ' -pentaCB.4。结果表明,3 -和4-MeSOィイD22摊位ィエD2 PCB同系物的代谢物抑制缝隙连接细胞间通讯测试大约在同一力量作为他们的父母的化合物。由于用多种肿瘤促进剂治疗后经常观察到细胞通讯的抑制，结果表明代谢物也可能起肿瘤促进剂的作用。结果表明,9个测试3 -和4-MeSOィイD22摊位ィエD2代谢物的四,五,hexaCBs减少throid在大鼠激素水平,这表明代谢产物可以作为endocrine-disrupters.6。结果表明，7种3-MeSO γ γ γ - D22 γ - D22 γ - pcbs和4- meso γ - D22 γ - D22 γ - D2-2,2′，4′，5,5′-pentaCB可能是由于UGT1A1和UGT1A6的诱导而导致血清T γ - D24 γ - D24 γ - D2葡萄糖醛酸化升高。少