Low-dose diethyldithiocarbamate attenuates the hepatotoxicity of 1,3-dichloro-2-propanol and selectively inhibits CYP2E1 activity in the rat.
The effect of low doses of diethyldithiocarbamate (DEDC) on hepatic cytochrome P450-dependent enzyme activity and 1,3-dichloro-2-propanol (DCP) hepatotoxicity in the rat have been investigated. DEDC at a dose of 5 mg/kg selectively inhibited enzyme markers for CYP2E1 activity, and provided substantial protection against DCP hepatotoxicity. At a higher dose (25 mg/kg), DEDC also inhibited an enzyme marker for CYP1A2 activity and provided complete protection against DCP hepatotoxicity. It is concluded: (a) that DEDC at a dose of 5 mg/kg is a selective CYP2E1 inhibitor in the rat in vivo; and (b) that DCP hepatotoxicity is mediated principally by CYP2E1, with a possible contribution from CYP1A2.
Stott
I
I
Department of Physiology and Pharmacology, Medical School, Queen's Medical Centre, Nottingham, UK.
Murthy
A
A
Robinson
A
A
Thomas
N W
NW
Fry
J R
JR
D000818:Animals; D003432:Cross-Linking Reagents / Q000633:toxicity*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004050:Ditiocarb / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D000517:alpha-Chlorohydrin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity
D003432:Cross-Linking Reagents; D065691:Cytochrome P-450 CYP2E1 Inhibitors; C033489:1,3-dichloro-2-propanol; D000517:alpha-Chlorohydrin; D004050:Ditiocarb