Involvement of cytochrome P4502E1 in the toxicity of dichloropropanol to rat hepatocyte cultures

Toxicology. 1997 Mar 28;118(2-3):171-9. doi: 10.1016/s0300-483x(96)03604-9.

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

  • 1-Propanol / toxicity
  • Acetone / analogs & derivatives
  • Acetone / toxicity
  • Analysis of Variance
  • Animals
  • Antidotes / pharmacology
  • Benzopyrans / toxicity
  • Cell Death / drug effects
  • Cells, Cultured
  • Chlorohydrins / metabolism
  • Chlorohydrins / toxicity*
  • Cytochrome P-450 CYP2E1 / biosynthesis*
  • Cytochrome P-450 CYP2E1 / metabolism
  • Cytochrome P-450 Enzyme System / metabolism
  • Ditiocarb / pharmacology
  • Drug Interactions
  • Enzyme Activation / drug effects
  • Enzyme Induction / drug effects
  • Glutathione / metabolism
  • Insecticides / toxicity
  • Isoniazid / toxicity
  • L-Lactate Dehydrogenase / metabolism
  • Liver / cytology
  • Liver / drug effects*
  • Liver / enzymology
  • Male
  • Mutagens / metabolism
  • Mutagens / toxicity*
  • Plants
  • Propanols
  • Rats
  • Rats, Wistar
  • alpha-Chlorohydrin / analogs & derivatives*
  • alpha-Chlorohydrin / metabolism
  • alpha-Chlorohydrin / toxicity

Substances

  • Antidotes
  • Benzopyrans
  • Chlorohydrins
  • Insecticides
  • Mutagens
  • Propanols
  • 1,3-dichloro-2-propanol
  • Acetone
  • precocene II
  • allyl alcohol
  • 2,3-dichloro-1-propanol
  • Cytochrome P-450 Enzyme System
  • alpha-Chlorohydrin
  • 1-Propanol
  • Ditiocarb
  • L-Lactate Dehydrogenase
  • Cytochrome P-450 CYP2E1
  • Glutathione
  • 1,3-dichloroacetone
  • Isoniazid