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

1.本研究结果表明，3-甲磺酰基-2，2‘，4’，5-四溴联苯(3-Meso_2-TetraBrB)对药物代谢酶的影响比母体TetraBrB或苯巴比妥高几千倍，而其同分异构体4-Meso_2-TetraBrB的作用不明显。这些结果表明，3-Meso_2-TetraBrB在TetraBrB诱导微粒体药物代谢酶中起重要作用。目前的研究结果表明，1，3-二氯苯(DCB)、1，2，4-三氯苯以及四、五和六氯联苯的9种Meso_2代谢物可降低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。上述结果提示，8种MesO_2-多氯联苯和3，5-二氯苯甲基砜均可引起小鼠血清T_4水平下降，可能是由于UGT1A1和UGT1A6的共同诱导，导致了肝脏T_4葡萄糖醛酸化作用的增强。DCB-，2，2‘，4’，5，5‘-五氯联苯、2，2’，3‘，4’，5，6-六氯联苯(HexaCB-)和Kanechlor500-(KC500-)处理的小鼠、仓鼠、大鼠和豚鼠的肝脏Meso_2代谢物浓度的差异与血清总T_4水平的下降无关。上述结果提示，DCB、HexaCB和KC500对大鼠、小鼠和豚鼠血清总T_4水平的降低作用至少部分是通过诱导肝T_4-UDP-葡萄糖醛酸基转移酶(T_4-UDP-GT)，尤其是UGT1A1和UGT1A6诱导T_4葡萄糖醛酸化作用来实现的，而对小鼠、金黄地鼠和大鼠血清总T_4水平的降低可能是通过其他机制实现的。

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.