Role of 3,4-dichlorophenyl methyl sulfone, a metabolite of o-dichlorobenzene, in the changes in hepatic microsomal drug-metabolizing enzymes caused by o-dichlorobenzene administration in rats.
2,3- and 3,4-Dichlorophenyl methyl sulfoxides and 2,3- and 3,4-dichlorophenyl methyl sulfones (2,3- and 3,4-DCPSO2Mes) were detected in the urine of rats administered o-dichlorobenzene (o-DCB). After administration of o-DCB to rats, swift decreases were observed in the concentrations of o-DCB in blood, liver, and kidneys, whereas 3,4-DCPSO2Me appeared in blood, liver, kidneys, and adipose tissue. The concentrations of 3,4-DCPSO2Me in the blood and three tissues reached maxima at 24 hr. Both aminopyrine N-demethylase and aniline hydroxylase activities and cytochrome P450 content of hepatic microsomes decreased 24 hr after administration of o-DCB. In contrast, 3,4-DCPSO2Me increased the activities of these enzymes and cytochrome P450 and b5 contents in rat liver microsomes. In both antibiotic-pretreated and bile duct-cannulated rats dosed with o-DCB, the concentrations of 2,3- and 3,4-DCPSO2Mes in blood, liver, kidneys, and adipose tissue were dramatically reduced. These findings suggest that the process of formation of methylsulfonyl metabolites of o-DCB involves biliary secretion of DCPSO2Mes and/or their precursors which will be subjected to metabolism by intestinal microflora. In antibiotic-pretreated rats, the inhibitory effects of o-DCB administration on the activities of aminopyrine- and aniline-metabolizing enzymes and the contents of cytochromes P450 and b5 in hepatic microsomes were greater than those observed in the intact rats. In bile duct-cannulated rats, the decrease in aminopyrine N-demethylase activity after administration of o-DCB was greater than that observed in the intact rats. These findings suggest that the apparent inhibition of drug-metabolizing enzymes by o-DCB is the result of simultaneous contrary effects, namely, the inductive effect of 3,4-DCPSO2Me and the stronger inhibitory effect of an unknown factor(s) on drug-metabolizing enzymes.
Kato
Y
Y
School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Kimura
R
R
D000633:Aminopyrine N-Demethylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D001652:Bile Ducts / Q000502:physiology; D002404:Catheterization; D002722:Chlorobenzenes / Q000378:metabolism* / Q000633:toxicity*; D002733:Chlorophenols / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007306:Insecticides / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D008698:Mesylates / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution / Q000187:drug effects
C107768:3,4-dichlorophenyl methyl sulfone; D000900:Anti-Bacterial Agents; D002722:Chlorobenzenes; D002733:Chlorophenols; D065607:Cytochrome P-450 Enzyme Inhibitors; D007306:Insecticides; D008698:Mesylates; C004726:2-dichlorobenzene; D003577:Cytochrome P-450 Enzyme System; D000633:Aminopyrine N-Demethylase