Kato Y, Yamada S, Sato M, Kimura R
School of Pharmaceutical Science, University of Shizuoka, Japan.
Toxicol Appl Pharmacol. 1993 Oct;122(2):214-21. doi: 10.1006/taap.1993.1190.
2,3,5- and 2,4,5-trichlorophenyl methyl sulfides, 2,3,5- and 2,4,5-trichlorophenyl methyl sulfoxides, and 2,3,5- and 2,4,5-trichlorophenyl methyl sulfones (TCPSO2Mes) were detected in the urine of rats dosed with 1,2,4-trichlorobenzene (TCB). After the administration of 1,2,4-TCB to rats, swift decreases in concentrations of 1,2,4-TCB in blood, liver, kidneys, and adipose tissue were observed. On the other hand, 2,3,5-TCPSO2Me appeared in blood, liver, kidneys, and adipose tissue and remained detectable in the blood and the three tissues until 120 hr. The increases in the activities of aminopyrine N-demethylase and aniline hydroxylase and the contents of cytochromes P450 and b5 in hepatic microsomes produced by 1,2,4-TCB occurred after increases in the hepatic concentration of 2,3,5-TCSO2Me. 2,3,5- and 2,4,5-TCPSO2Me increased the above four parameters in rat liver microsomes. The inducing intensity of 2,3,5-TCPSO2Me was much higher than that of 2,4,5-TCPSO2Me. 2,3,5-TCPSO2Me was considered to be a potent inducer and to play a principal role in the induction by 1,2,4-TCB. When 1,2,4-TCB was injected ip into bile duct-cannulated rats, little 2,3,5-TCPSO2Me was detected in blood, liver, kidneys, and adipose tissue. In the antibiotic-pretreated rats dosed with 1,2,4-TCB, 2,3,5-TCPSO2Me concentrations in the blood and the three tissues markedly decreased. These findings suggest that the formation of methylsulfonyl metabolites from 1,2,4-TCB depends largely upon the metabolism of some precursor(s) excreted in the bile by intestinal microflora. The increasing effects of 1,2,4-TCB administration on the activities of aminopyrine- and aniline-metabolizing enzymes and the contents of cytochromes P450 and b5 in hepatic microsomes were not observed in the bile duct-cannulated rats. These findings provide evidence that the induction of drug-metabolizing enzymes by 1,2,4-TCB is not due to the action of 1,2,4-TCB itself but is due to its methylsulfonyl metabolite, 2,3,5-TCPSO2Me.
在给大鼠投喂1,2,4-三氯苯（TCB）后，在其尿液中检测到了2,3,5-和2,4,5-三氯苯基甲基硫醚、2,3,5-和2,4,5-三氯苯基甲基亚砜以及2,3,5-和2,4,5-三氯苯基甲基砜（TCPSO2Mes）。给大鼠施用1,2,4-TCB后，观察到血液、肝脏、肾脏和脂肪组织中1,2,4-TCB的浓度迅速下降。另一方面，2,3,5-TCPSO2Me出现在血液、肝脏、肾脏和脂肪组织中，并且在血液和这三个组织中直到120小时仍可检测到。1,2,4-TCB引起的肝微粒体中氨基比林N-脱甲基酶和苯胺羟化酶活性以及细胞色素P450和b5含量的增加发生在肝脏中2,3,5-TCSO2Me浓度增加之后。2,3,5-和2,4,5-TCPSO2Me增加了大鼠肝微粒体中的上述四个参数。2,3,5-TCPSO2Me的诱导强度远高于2,4,5-TCPSO2Me。2,3,5-TCPSO2Me被认为是一种强效诱导剂，在1,2,4-TCB的诱导中起主要作用。当将1,2,4-TCB腹腔注射到胆管插管的大鼠中时，在血液、肝脏、肾脏和脂肪组织中几乎检测不到2,3,5-TCPSO2Me。在预先用抗生素处理并投喂1,2,4-TCB的大鼠中，血液和这三个组织中的2,3,5-TCPSO2Me浓度显著降低。这些发现表明，1,2,4-TCB甲基砜代谢物的形成很大程度上取决于肠道微生物群从胆汁中排泄的某些前体的代谢。在胆管插管的大鼠中未观察到施用1,2,4-TCB对肝微粒体中氨基比林和苯胺代谢酶活性以及细胞色素P450和b5含量的增加作用。这些发现提供了证据，证明1,2,4-TCB对药物代谢酶的诱导不是由于1,2,4-TCB本身的作用，而是由于其甲基砜代谢物2,3,5-TCPSO2Me的作用。
