Evidence that Cytochrome P-4502E1 Contributes to Ethanol Elimination at Low Doses: Effects of Diallyl Sulfide and 4-Methyl Pyrazole on Ethanol Elimination in the Perfused Rat Liver

The roles of cytochrome P-4502E1 and alcohol dehydrogenase (ADH) on ethanol (EtOH) hepatic elimination was examined in the perfused rat liver. EtOH concentration-time curves of outflow after instantaneous administration (0.46 mg) through the portal vein with or without perfusion of diallyl sulfide (DAS), a selective cytochrome P-4502E1 inhibitor, and/or 4-methyl pyrazole (4-MP), a classical ADH inhibitor, were analyzed by the statistical moment analysis and the compartment dispersion model. Recovery ratios obtained by moment analysis significantly changed with perfusion of inhibitors ( p < 0.01). Values of the hepatic volume of distribution and the relative dispersion were significantly higher by the perfusion of DAS and 4-MP ( p < 0.01). In the two-compartment dispersion model, the partition ratio ( K ') and the first-order elimination constant ( K _e) were decreased significantly by DAS ( p < 0.05). By the addition of 4-MP, the blood volume of distribution ( V _B ) and the backward partition rate constant ( k ₂₁) were increased significantly ( p < 0.05). K _e values were decreased significantly to 0 ( p < 0.001). The decrease of elimination rates by DAS and/or 4-MP shows the inhibition of metabolic pathways. The change of V _B and k ₂₁ caused by DAS and 4-MP indicates that EtOH taken into hepatic tissues was not metabolized and flowed out into the perfusates. Inhibition rates calculated from the efficiency number with addition of DAS and DAS + 4-MP were 40.7 and 99.3%. Therefore, cytochrome P-4502E1 and ADH accounted for 40 and 60% of the hepatic EtOH elimination at low doses.