title: Involvement of cytochrome P4502E1 in the toxicity of dichloropropanol to rat hepatocyte cultures.
abstract: Hepatocytes were isolated and cultured from untreated rats and rats treated with isoniazid to induce cytochrome P4502E1. Isoniazid selectively increased p-nitrophenol hydroxylase activity in 2-h cultures, and increased the toxicity of both 1,3- and 2,3-dichloropropanol. Isoniazid also increased the rate and extent of glutathione depletion by the dichloropropanols. There was no effect of isoniazid on the toxicity of 1,3-dichloroacetone, precocene II or allyl alcohol. In addition, diethyldithiocarbamate selectively inhibited p-nitrophenol hydroxylase in 2-h cultures from untreated and isoniazid-treated rats, as well as abolishing toxicity of the dichloropropanols. In 24-h cultures from isoniazid-treated rats diethyldithiocarbamate inhibited high affinity MCOD activity by 55% and there was also a small but significant inhibition of precocene II toxicity. These results indicate that isoniazid-inducible P4502E1 can mediate the toxicity of dichloropropanol.
authors.affiliation: Department of Physiology and Pharmacology, Queen's Medical Centre, Nottingham, UK.
authors.forename: A H
authors.initials: AH
authors.lastname: Hammond
authors.forename: J R
authors.initials: JR
authors.lastname: Fry
mesh_terms: D000433:1-Propanol / Q000633:toxicity; D000096:Acetone / Q000031:analogs & derivatives / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D001578:Benzopyrans / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002728:Chlorohydrins / Q000378:metabolism / Q000633:toxicity*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004050:Ditiocarb / Q000494:pharmacology; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity; D007538:Isoniazid / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D010944:Plants; D020005:Propanols; D051381:Rats; D017208:Rats, Wistar; D000517:alpha-Chlorohydrin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity
chemical_list: D000931:Antidotes; D001578:Benzopyrans; D002728:Chlorohydrins; D007306:Insecticides; D009153:Mutagens; D020005:Propanols; C033489:1,3-dichloro-2-propanol; D000096:Acetone; C014163:precocene II; C006463:allyl alcohol; C076159:2,3-dichloro-1-propanol; D003577:Cytochrome P-450 Enzyme System; D000517:alpha-Chlorohydrin; D000433:1-Propanol; D004050:Ditiocarb; D007770:L-Lactate Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione; C047675:1,3-dichloroacetone; D007538:Isoniazid