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。本研究的结果表明，3-甲基磺酰基-2、2'，4'，5-四邻苯甲酰基（3-Meso_2-tetrabrb）对药物代谢酶，cyp2b1和cyp2b2的药物的影响，比亲本tetrabrb或phenterbrb或phenerobbalbial temomem高几千倍。 4-Meso_2-tetrabRB不是2。目前的结果表明，3-Meso_2-tetrabRB在Tetrabrb.3诱导微粒体药物代谢酶中起重要作用。目前的发现表明，1、3-氯苯（DCB），1、2、2、4-三氯 - 苯苯和四氯 - ，五氯苯基，五氯苯基和六氯苯基的九MESO_2代谢产物降低了大鼠的甲状腺激素水平，这表明该代理可能会像内代代理。目前的结果表明，在施用八个Meso_2-氯化双苯基和3，5，5-二氯苯基甲基硫酮后，肝甲状腺素（T_4）葡萄糖醛酸化的增加可能是因为诱导UGT1A1和UGT1A6导致了血清T_4级别的降低。 dcb-，2，2'，4'，5，5'pentachlorobiphenyl-（pentacb-），2，2'，3'，3'，4'，4'，5，5，5，5，5，5，6-氯位苯基（Hexacb--）和kanechlor-50000-（KANECHLOR-50000-（KC50000-）猪与血清总T_4水平的降低无关。6。目前的发现表明，在大鼠，小鼠和猪中，DCB，HexAcB和KC500的血清总T_4水平分别降低至少部分是由于T_4葡萄糖蛋白通过诱导而通过肝T_4-udp-udp-udp-udp-glucuronosylassylansferase（t_4-ugt and ugty and ugt and ugt and ugt and ugt and ugt and ugty and fugt-ugt and t_4- ugt）降低。 PentacB，TetrabRB和KC500的血清总T_4水平，仓鼠和大鼠可能通过替代机制发生。