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 CCI4 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.