Mechanism of inhibition of hepatic bioactivation of paracetamol by dimethyl sulfoxide.
Prior work has shown that DMSO inhibits paracetamol hepatotoxicity. In this paper we show that DMSO and its reduced metabolite dimethyl sulfide (DMS) can inhibit in vitro hepatic dimethylnitrosamine N-demethylase. We also show that DMSO can inhibit in vivo production of glutathione conjugates of paracetamol. Glutathione is known to conjugate the bioactivated form of paracetamol. Also, the isozyme of cytochrome P-450 responsible for dimethylnitrosomine N-demethylase, cytochrome P-450j, is thought responsible for paracetamol bioactivation. We therefore propose that DMSO inhibits paracetamol hepatotoxicity due to inhibition of cytochrome P-450j-dependent paracetamol bioactivation by DMSO and its metabolite DMS.
Jeffery
E H
EH
Institute for Environmental Studies, University of Illinois, Urbana 61801.
Arndt
K
K
Haschek
W M
WM
D000082:Acetaminophen / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D001711:Biotransformation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D004128:Dimethylnitrosamine / Q000378:metabolism; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D013431:Sulfates / Q000378:metabolism
D005965:Glucuronates; D013431:Sulfates; D000082:Acetaminophen; D005978:Glutathione; D004128:Dimethylnitrosamine; D004121:Dimethyl Sulfoxide