Evidence that methylsulfonyl metabolites of m-dichlorobenzene are causative substances of induction of hepatic microsomal drug-metabolizing enzymes by the parent compound in rats

Abstract

This study was undertaken to clarify the relationship between the formation of 2,4- and 3,5-dichlorophenyl methyl sulfones, metabolites of m-dichlorobenzene (DCB), and their inducing effect on hepatic microsomal drug-metabolizing enzymes in rats. When m-DCB was injected ip into bile duct-cannulated rats, little or no methyl sulfones were detected in blood, liver, kidneys, adipose tissue, or bile. In the antibiotic-pretreated rats dosed with m-DCB, metabolite concentrations in the blood and the three tissues markedly decreased. These findings suggest that the formation of methylsulfonyl metabolites from m-DCB depends largely upon the metabolism of some precursor(s) excreted in the bile by intestinal microflora. The increasing effects of m-DCB administration on the activities of aminopyrine and aniline metabolizing enzymes and the contents of cytochromes P-450 and b5 in hepatic microsomes were scarcely observed in the bile duct-cannulated and antibiotic-pretreated rats, in which the drug-metabolizing enzymes were able to be induced by phenobarbital treatment. On the other hand, in rats administered 2,4- or 3,5-dichlorophenyl methyl sulfone hepatic distribution of each methyl sulfone was similar to that in intact rats, and the degree of increase of the above four parameters was nearly the same as that in the intact rats. These findings provide evidence that the induction of drug-metabolizing enzymes by m-DCB is not due to the action of m-DCB but is due to its methylsulfonyl metabolites.