Effects of disulfiram on hepatic P450IIE1, other microsomal enzymes, and hepatotoxicity in rats

John F. Brady, Fang Xiao, Mong-Heng Wang, Yan Li, Shu M. Ning, Jeanne M. Gapac, Chung S. Yang

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

Disulfiram, widely used in avoidance therapy for alcohol abuse, has been shown to have protective effects against chemically induced toxicity and carcinogenesis. The purpose of this work was to elucidate the biochemical mechanisms of this protective action by examining its effects on cytochrome P450IIE1 and other related microsomal enzyme activities. When a dose of disulfiram was given intragastrically to rats, a very rapid decrease of N-nitrosodimethylamine (NDMA) demethylase activity, possibly due to the inactivation of P450IIE1, was seen. The loss of P450IIE1 protein from the microsomal membrane was observed at 18 hr after receiving disulfiram, but not within the first 5 hr after the treatment. P450IIB1, on the other hand, was induced markedly between 15 and 72 hr after the disulfiram treatment. The treatment, however, caused only moderate changes in some other P450 isozymes. Carbon disulfide, a putative metabolite of disulfiram, produced similar effects on P450IIE1, but with shorter duration. Carbon disulfide, however, did not induce P450IIB1. Diethyldithiocarbamate, a reductive product of disulfiram, was an inhibitor of P450IIE1 activity in vitro, and upon preincubation with microsomes, it produced an NADPH-dependent inactivation of NDMA demethylase activity. The results suggest that this or other metabolites of disulfiram are inhibitors of P450IIE1 and are responsible for the inactivation of P450IIE1 in vivo. Hepatotoxicity of NDMA or CCl4 in rats was blocked by pretreatment with disulfiram. The present work demonstrates that P450IIE1 was inhibited and inactivated by disulfiram, and this mechanism can account for many of the reported inhibitory actions of disulfiram against chemically induced toxicity and carcinogenesis.

Original languageEnglish (US)
Pages (from-to)366-373
Number of pages8
JournalToxicology and Applied Pharmacology
Volume108
Issue number2
DOIs
StatePublished - Jan 1 1991
Externally publishedYes

Fingerprint

Disulfiram
Rats
Liver
Enzymes
Carbon Disulfide
Cytochrome P-450 CYP2E1
Metabolites
Toxicity
Carcinogenesis
Ditiocarb
Dimethylnitrosamine
Enzyme activity
Cytochromes
Microsomes
NADP
Alcoholism
Isoenzymes
Membrane Proteins
Alcohols
Membranes

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Effects of disulfiram on hepatic P450IIE1, other microsomal enzymes, and hepatotoxicity in rats. / Brady, John F.; Xiao, Fang; Wang, Mong-Heng; Li, Yan; Ning, Shu M.; Gapac, Jeanne M.; Yang, Chung S.

In: Toxicology and Applied Pharmacology, Vol. 108, No. 2, 01.01.1991, p. 366-373.

Research output: Contribution to journalArticle

Brady, John F. ; Xiao, Fang ; Wang, Mong-Heng ; Li, Yan ; Ning, Shu M. ; Gapac, Jeanne M. ; Yang, Chung S. / Effects of disulfiram on hepatic P450IIE1, other microsomal enzymes, and hepatotoxicity in rats. In: Toxicology and Applied Pharmacology. 1991 ; Vol. 108, No. 2. pp. 366-373.
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abstract = "Disulfiram, widely used in avoidance therapy for alcohol abuse, has been shown to have protective effects against chemically induced toxicity and carcinogenesis. The purpose of this work was to elucidate the biochemical mechanisms of this protective action by examining its effects on cytochrome P450IIE1 and other related microsomal enzyme activities. When a dose of disulfiram was given intragastrically to rats, a very rapid decrease of N-nitrosodimethylamine (NDMA) demethylase activity, possibly due to the inactivation of P450IIE1, was seen. The loss of P450IIE1 protein from the microsomal membrane was observed at 18 hr after receiving disulfiram, but not within the first 5 hr after the treatment. P450IIB1, on the other hand, was induced markedly between 15 and 72 hr after the disulfiram treatment. The treatment, however, caused only moderate changes in some other P450 isozymes. Carbon disulfide, a putative metabolite of disulfiram, produced similar effects on P450IIE1, but with shorter duration. Carbon disulfide, however, did not induce P450IIB1. Diethyldithiocarbamate, a reductive product of disulfiram, was an inhibitor of P450IIE1 activity in vitro, and upon preincubation with microsomes, it produced an NADPH-dependent inactivation of NDMA demethylase activity. The results suggest that this or other metabolites of disulfiram are inhibitors of P450IIE1 and are responsible for the inactivation of P450IIE1 in vivo. Hepatotoxicity of NDMA or CCl4 in rats was blocked by pretreatment with disulfiram. The present work demonstrates that P450IIE1 was inhibited and inactivated by disulfiram, and this mechanism can account for many of the reported inhibitory actions of disulfiram against chemically induced toxicity and carcinogenesis.",
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