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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09680531/
• 关键词: PCB; methylsulfonyl metabolite; CYP2B1; 2; induction; thyroid hormone; UDP-glucuronosyltransferase; cell communication; rat; 薬物代謝酵素; δ-アミノレブリン酸合成酵素; non-planar PCB; coplanar PCB; mono-ortho-置換 PCB; PB型誘導作用; PB誘導性P450分子種; ギャップ結合細胞間コミュニケーション

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-甲磺酰(3-ィイD22ィエD2)代谢产物在多氯联苯(PCb)同系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-ィイD22-ィエD2代谢物的生物活性和毒理学效应。我们合成了11个3-MesoィイD22ィエD2和两个4-MesoィイD22ィエD2代谢物(据报道，它们残留在人乳、肝脏、脂肪组织和几种哺乳动物的组织中)，以及它们两个结构相似的3-MesoィイD22ィエD2-PCBS。本研究结果表明，所研究的3-MesoィイD22ィエD2衍生物存在结构-CYP2B1/2诱导关系。结果表明，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’-…)对雌雄大鼠肝脏药物代谢酶均具有较强的苯巴比妥(PB)型诱导剂作用。此外，3-MesoィイD22ィエD2-2，2‘，4’，5，5‘-五氯联苯对药物代谢酶活性的诱导没有性别差异。4-MesoィイD22ィエD2异构体对雌雄大鼠均无明显影响。结果表明，2，2‘，4，5，5’-五氯苯对某些药物代谢酶和δ-氨基乙酰丙酸合成酶的诱导作用不是2，2‘，4，5，5’-五氯苯本身的作用，而是其3-甲磺酰代谢物3-ィイD22ィエD2-2，2‘，4’，5，5‘-五氯苯的作用。结果表明，被测试的多氯联苯同系物的3-和4-MesoィイD22ィエD2代谢物抑制缝隙连接细胞间通讯的效力与其亲本化合物大致相同。由于许多促癌剂治疗后经常观察到细胞通讯的抑制，结果提示代谢产物也可能作为促癌剂发挥作用。结果表明，所测试的9种四、五和六氯联苯的3-和4-中位ィイD22ィエD2代谢物降低了大鼠的甲状腺激素水平，提示这些代谢物可能是内分泌干扰物。结果表明，7种3-MesoィイD22ィエD2-ィエ和4-MesoィイD22ィエD2-2，2‘，4’，5，5‘-五氯联苯均可引起小鼠血清T-ィイD24ィエD2水平的降低，其原因可能是由于UGT1A1和UGT1A6的共同诱导，导致肝组织甲状腺激素(TィイD24ィエD2)糖醛酸化水平升高。较少

项目成果

Yoshihisa Kato: "The induction of hepatic microsomal UDP-glucuronosyltransferase by the methylsulfonyl metabolites of polychlorinated biphenyl congeners in rats"Chem, -Biol. Interact.. 125. 107-115 (2000)

Yoshihisa Kato：“大鼠体内多氯联苯同系物的甲磺酰代谢物诱导肝微粒体 UDP-葡萄糖醛酸基转移酶”Chem，-Biol。

Yoshihisa Kato: "Evidence that 3-methylsulfonyl metabolite of 2,2',4,5,5'-pentachlorobiphenyl is causative substance of induction of hepatic microsomal drug-metabolizing enzymes by the parent compound in rats."Jpn J. Toxicol. Environ. Health. 44. 40 (1998

Yoshihisa Kato：“有证据表明 2,2,4,5,5-五氯联苯的 3-甲磺酰代谢物是母体化合物在大鼠中诱导肝微粒体药物代谢酶的致病物质。”Jpn J. Toxicol。

Koichi Haraguchi: "Hydroxylation and methylthiolation of mono-ortho-substituted polychlori-nated biphenyls in rats: Identification of metabolites with tissue affinity" Chem.Res.Toxicol.11. 1508-1515 (1998)

Koichi Haraguchi：“大鼠中单邻位取代的多氯联苯的羟基化和甲硫基化：具有组织亲和力的代谢物的鉴定”Chem.Res.Toxicol.11。

Koichi Haraguchi: "Comparative metabolism of polychlorinated biphenyls with 2,4,5-trichloro substitution in rats : Regioselective formation of hydroxy metabolites with high blood affinity"Organohalogen Compounds. 37. 401-404 (1998)

Koichi Haraguchi：“大鼠体内 2,4,5-三氯取代的多氯联苯的比较代谢：具有高血液亲和力的羟基代谢物的区域选择性形成”有机卤素化合物。

Koichi Haraguchi: "Tissue distribution of methylsulfonyl metabolites derived from of 2,2',4,4'-,3,3',4,4'-2,3',4',5-tetrachlorobiphenyls in rats."Jpn. J. Toxicol. Environ. Health. 44. 42 (1998)

Koichi Haraguchi：“源自 2,2,4,4-,3,3,4,4-2,3,4,5-四氯联苯的甲磺酰代谢物在大鼠体内的组织分布。”