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Methylsulfonyl metabolites of polychlorinated biphenyl and polybrominated biphenyl as disrupters of endocrine action

多氯联苯和多溴联苯的甲磺酰代谢物作为内分泌作用的干扰物

基本信息

批准号：
12680549
负责人：
KATO Yoshihisa
金额：
$ 2.43万
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：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

1. The results from the present study show that the effects of 3-methylsulfonyl-2, 2', 4', 5-tetrabromobiphenyl (3-MeSO_2-TetraBrB) on the drug-metabolizing enzymes, CYP2B1 and CYP2B2, are several thousand-fold higher than those of parent TetraBrB or phenobarbital, while the effects of its isomeric 4-MeSO_2-TetraBrB are not.2. The present results suggest that 3-MeSO_2-TetraBrB plays an important role in the induction of microsomal drug-metabolizing enzymes by TetraBrB.3. The present findings show that the nine MeSO_2 metabolites of 1, 3-dichlorobenzene (DCB), 1, 2, 4-trichloro-benzene, and tetra-, penta- and hexachlorobiphenyls reduce thyroid hormone levels in rats, suggesting that the metabolites may act as endocrine-disrupters.4. The present results indicate that increase in the hepatic thyroxine (T_4) glucuronidation after the administration of the eight MeSO_2-polychlorinated biphenyls and 3, 5-dichlorophenyl methyl sulfone possibly because of the induction of both UGT1A1 and UGT1A6 caused the reduction of serum T_4 levels.5. The difference in total hepatic concentration of MeSO_2 metabolites among DCB-, 2, 2', 4', 5, 5'-pentachlorobiphenyl-(PentaCB-), 2, 2', 3', 4', 5, 6-hexachlorobiphenyl- (HexaCB-) and Kanechlor-500- (KC500-) treated mice, hamsters, tats and guinea pigs was not correlated with that in the decrease in serum total T_4 level.6. The present findings suggest that the reduction of serum total T_4 level by DCB, HexaCB and KC500 in rats, mice and guines pigs, respectively, would occur at least in part by an increase in T_4 glucuronidation through the induction of hepatic T_4-UDP-glucuronosyltransferase (T_4-UDP-GT), especially UGT1A1 and UGT1A6, while the decrease of serum total T_4 level by PentaCB, TetraBrB and KC500 in mice, hamsters and rats may occur through alternative mechanisms.

1. 本研究结果表明，3-甲基磺酰基- 2,2′，4′，5-四溴联苯（3-MeSO_2-TetraBrB）对药物代谢酶CYP2B1和CYP2B2的影响比亲本TetraBrB或苯巴比多高几千倍，而其异构体4- meso_2 -TetraBrB的影响则没有。目前的结果表明，3-MeSO_2-TetraBrB在诱导微粒体药物代谢酶中起重要作用。本研究结果表明，1,3 -二氯苯（DCB）、1,2,4 -三氯苯和四、五、六氯联苯的九种MeSO_2代谢物可降低大鼠甲状腺激素水平，提示这些代谢物可能具有内分泌干扰物的作用。结果表明，8种meso_2 -多氯联苯和3,5 -二氯苯基甲基砜处理后肝脏甲状腺素（T_4）葡萄糖醛酸化升高可能是由于UGT1A1和UGT1A6的诱导导致血清T_4水平降低。DCB-、2,2′、4′、5,5′-五氯联苯-(PentaCB-)、2,2′、3′、4′、5,6 -六氯联苯-(HexaCB-)和kanechor -500- (KC500-)处理小鼠、仓鼠和豚鼠肝脏中MeSO_2代谢物总浓度的差异与血清总T_4水平的降低无关。本研究结果表明，DCB、HexaCB和KC500对大鼠、小鼠和豚鼠血清总T_4水平的降低，至少部分是通过诱导肝脏T_4- udp -葡萄糖醛酸转移酶（T_4- udp - gt），尤其是UGT1A1和UGT1A6，增加T_4糖醛酸糖醛酸化而发生的，而PentaCB、TetraBrB和KC500对小鼠、仓鼠和大鼠血清总T_4水平的降低可能是通过其他机制发生的。