Effects of chlorobenzenes and their methyl sulfone metabolites on microsomal enzymes associated with drug metabolism in rat liver.
The effects of m- and o-dichlorobenzenes (DCBs), 1,2,4-trichlorobenzene (TCB) and their methylsulfonyl metabolites on the activities of hepatic microsomal reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome c reductase, reduced nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase and uridine diphosphate (UDP)-glucuronyltransferase (UDPGT) were studied. The treatment of rats with m-DCB, 1,2,4-TCB, 2,4-, 3,5- or 3,4-dichlorophenyl methyl sulfone (DCPSO2Me) or 2,4,5-trichlorophenyl methyl sulfone (TCPSO2Me) significantly increased NADPH-cytochrome c reductase activity, but o-DCB had no effect on this enzyme activity. All three chlorinated benzenes slightly reduced NADH-cytochrome b5 reductase activity, whereas the methylsulfonyl compounds elicited no change in the enzyme activity. Treatments with m- and o-DCBs, 1,2,4-TCB and 2,4,5-TCPSO2Me enhanced UDPGT activities toward both chloramphenicol (CP) and p-nitrophenol (NP). 2,4-, 3,5- and 3,4-DCPSO2Mes increased the activity of UDPGT toward CP but not toward p-NP. These findings concerning the effects of 2,4-, 3,5- and 3,4-DCPSO2Mes on the activities of NADPH-cytochrome c reductase and UDPGT support our hypothesis that the methylsulfonyl metabolites derived from m- and o-DCBs are phenobarbital-type inducers of the hepatic microsomal drug-metabolizing enzymes. It is concluded that the methyl sulfone derivatives of m- and o-DCBs and 1,2,4-TCB are inducers of phase I reactions in hepatic microsomal drug metabolism, and they have increasing effects on the phase II enzyme activities, such as UDPGT. Thus, the methyl sulfones seem to play an important role in the inducing effects of their parent compounds, m- and o-DCBs and 1,2,4-TCB, on the drug-metabolizing enzyme systems.
Kato
Y
Y
School of Pharmaceutical Science, University of Shizuoka, Japan.
Kogure
T
T
Sato
M
M
Kimura
R
R
D000818:Animals; D002722:Chlorobenzenes / Q000494:pharmacology*; D004790:Enzyme Induction; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000096:biosynthesis; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013450:Sulfones / Q000494:pharmacology*
D002722:Chlorobenzenes; D013450:Sulfones; C009947:1,2,4-trichlorobenzene; D008748:Methylcholanthrene; C004726:2-dichlorobenzene; C042146:1,3-dichlorobenzene; D009245:NADH Dehydrogenase; D014453:Glucuronosyltransferase; D010634:Phenobarbital