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

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Abstract
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 (Ke) were decreased significantly by DAS (p < 0.05). By the addition of 4-MP, the blood volume of distribution (VB) and the backward partition rate constant (k21) were increased significantly (p < 0.05). Ke 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 VB and k21 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.