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-450E1 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 (K0) 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). K sigma 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 beta 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.
Matsumoto
H
H
Department of Legal Medicine, Kyoto University Faculty of Medicine, Japan.
Matsubayashi
K
K
Fukui
Y
Y
D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors* / Q000502:physiology; D000498:Allyl Compounds; D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000493:pharmacokinetics*; D000077604:Fomepizole; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008962:Models, Theoretical; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors* / Q000502:physiology; D010477:Perfusion; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013440:Sulfides / Q000494:pharmacology*
D000498:Allyl Compounds; D065607:Cytochrome P-450 Enzyme Inhibitors; D011720:Pyrazoles; D013440:Sulfides; D000431:Ethanol; C038491:allyl sulfide; D000077604:Fomepizole; D003577:Cytochrome P-450 Enzyme System; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating