Role of 2,3,5-Trichlorophenyl Methyl Sulfone, a Metabolite of 1,2,4-Trichlorobenzene, in the Induction of Hepatic Microsomal Drug-Metabolizing Enzymes by 1,2,4-Trichlorobenzene in Rats

Abstract

2,3,5- and 2,4,5-trichiorophenyl methyl sulfides, 2,3,5- and 2,4,5-trichlorophenyl methyl sulfoxides, and 2,3,5- and 2,4,5-trichlorophenyl methyl sulfones (TCPSO 2Mes) 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-TCPSO 2Me 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 b 5 in hepatic microsomes produced by 1,2,4-TCB occurred after increases in the hepatic concentration of 2,3,5-TCPSO 2Me. 2,3,5- and 2,4,5-TCPSO 2Me increased the above four parameters in rat liver microsomes. The inducing intensity of 2,3,5-TCPSO 2Me was much higher than that of 2,4,5-TCPSO 2Me. 2,3,5-TCPSO 2Me was considered to be a potent inducer and to play a principal role in the induction by l,2,4-TCB. When l,2,4-TCB was injected ip into bile duct-cannulated rats, little 2,3,5-TCPSO 2Me was detected in blood, liver, kidneys, and adipose tissue. In the antibiotic-pretreated rats dosed with 1,2,4-TCB, 2,3,5-TCPSO 2Me 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 b 5 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-TCPSO 2Me.