Involvement of cytochrome P4502E1 in the toxicity of dichloropropanol to rat hepatocyte cultures.
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.
Hammond
A H
AH
Department of Physiology and Pharmacology, Queen's Medical Centre, Nottingham, UK.
Fry
J R
JR
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
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