Effects of carbon disulfide, diethyldithiocarbamate, and disulfiram on drug metabolism in the perfused rat liver.

The effects of carbon disulfide (CS2), diethyldithiocarbamate (DTC) and disulfiram (DS) on hepatic drug metabolism were studied in a noncirculating and hemoglobin-free rat liver perfusion system using p-nitroanisole (p-NA) as a substrate. Infusion of 1 mumol of CS2 into a normal rat liver instantaneously lowered the free p-nitrophenol (p-NP) concentration in the effluent perfusate; however, the effects on the levels of its glucuronide and sulfate conjugates were much less marked. The suppression of p-NP production by CS2 was also observed in livers isolated from phenobarbital (PB)- and 3-methylcholanthrene (3-MC)-treated rats; to a greater extent, in the normal and 3-MC groups. Partial recovery was observed in the normal and PB-treated groups, but it was slow and slight in the 3-MC-treated group. Infusion of DTC, up to 20 mumol, did not lower free p-NP levels, but a slight transient increase was noted, especially in the 3-MC-group. Using 50 mumol of DTC, a slight suppression resulted. DS, up to 20 mumol, did not decrease p-NP production, but rather gradually increased it, especially in the 3-MC-treated groups. Without the p-NP infusion, about 60-70% of the infused DS (10 mumol) was recovered in the effluent perfusate as DTC plus its glucuronide conjugate, the formation of the latter being greatly enhanced by the inducer treatments and markedly suppressed during the p-NP infusion. In this paper, these results are discussed with regards to the mechanisms of drug metabolism inhibition by DS administration.