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.
MeSH terms
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1-Propanol / toxicity
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Acetone / analogs & derivatives
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Acetone / toxicity
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Analysis of Variance
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Animals
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Antidotes / pharmacology
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Benzopyrans / toxicity
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Cell Death / drug effects
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Cells, Cultured
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Chlorohydrins / metabolism
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Chlorohydrins / toxicity*
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Cytochrome P-450 CYP2E1 / biosynthesis*
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Cytochrome P-450 CYP2E1 / metabolism
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Cytochrome P-450 Enzyme System / metabolism
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Ditiocarb / pharmacology
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Drug Interactions
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Enzyme Activation / drug effects
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Enzyme Induction / drug effects
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Glutathione / metabolism
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Insecticides / toxicity
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Isoniazid / toxicity
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L-Lactate Dehydrogenase / metabolism
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Liver / cytology
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Liver / drug effects*
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Liver / enzymology
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Male
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Mutagens / metabolism
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Mutagens / toxicity*
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Plants
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Propanols
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Rats
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Rats, Wistar
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alpha-Chlorohydrin / analogs & derivatives*
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alpha-Chlorohydrin / metabolism
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alpha-Chlorohydrin / toxicity
Substances
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Antidotes
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Benzopyrans
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Chlorohydrins
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Insecticides
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Mutagens
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Propanols
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1,3-dichloro-2-propanol
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Acetone
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precocene II
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allyl alcohol
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2,3-dichloro-1-propanol
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Cytochrome P-450 Enzyme System
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alpha-Chlorohydrin
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1-Propanol
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Ditiocarb
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L-Lactate Dehydrogenase
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Cytochrome P-450 CYP2E1
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Glutathione
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1,3-dichloroacetone
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Isoniazid