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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
Author(s) -
Matsumoto Hiroshi,
Matsubayashi Keiko,
Fukui Yuko
Publication year - 1996
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.1996.tb01719.x
Subject(s) - chemistry , ethanol , elimination rate constant , alcohol dehydrogenase , volume of distribution , cytochrome , perfusion , cytochrome p450 , stereochemistry , biochemistry , metabolism , pharmacokinetics , pharmacology , medicine , enzyme , biology
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.