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

被引:27
作者
Matsumoto, H
Matsubayashi, K
Fukui, Y
机构
[1] Department of Legal Medicine, Kyoto University, Faculty of Medicine, Kyoto
[2] Department of Legal Medicine, Kyoto University, Faculty of Medicine
关键词
ethanol elimination; alcohol dehydrogenase; cytochrome P-4502E1; dispersion model; rat liver;
D O I
10.1111/j.1530-0277.1996.tb01719.x
中图分类号
R194 [卫生标准、卫生检查、医药管理];
学科分类号
摘要
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-theta) 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-theta 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.
引用
收藏
页码:A12 / A16
页数:5
相关论文
共 25 条
[1]  
BRADFORD BU, 1993, MOL PHARMACOL, V43, P115
[2]   MODULATION OF RAT HEPATIC-MICROSOMAL MONOOXYGENASE ENZYMES AND CYTOTOXICITY BY DIALLYL SULFIDE [J].
BRADY, JF ;
WANG, MH ;
HONG, JY ;
XIAO, F ;
LI, Y ;
YOO, JSH ;
NING, SM ;
LEE, MJ ;
FUKUTO, JM ;
GAPAC, JM ;
YANG, CS .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1991, 108 (02) :342-354
[3]  
BRADY JF, 1988, CANCER RES, V48, P5937
[4]   INHIBITORY EFFECT OF 4-METHYLPYRAZOLE ON ANTIPYRINE CLEARANCE IN RATS [J].
CHOW, HH ;
HUTCHALEELAHA, A ;
MAYERSOHN, M .
LIFE SCIENCES, 1992, 50 (09) :661-666
[5]   OXIDATION OF PYRAZOLE BY RECONSTITUTED SYSTEMS CONTAINING CYTOCHROME-P-450 IIE1 [J].
CLEJAN, LA ;
CEDERBAUM, AI .
BIOCHIMICA ET BIOPHYSICA ACTA, 1990, 1034 (02) :233-237
[6]   THE D(V-K) ISOTOPE EFFECT OF THE CYTOCHROME P-450-MEDIATED OXIDATION OF ETHANOL AND ITS BIOLOGICAL APPLICATIONS [J].
DAMGAARD, SE .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1982, 125 (03) :593-603
[7]   A 2-COMPARTMENT DISPERSION MODEL DESCRIBES THE HEPATIC OUTFLOW PROFILE OF DICLOFENAC IN THE PRESENCE OF ITS BINDING-PROTEIN [J].
EVANS, AM ;
HUSSEIN, Z ;
ROWLAND, M .
JOURNAL OF PHARMACY AND PHARMACOLOGY, 1991, 43 (10) :709-714
[8]  
FUJIMIYA T, 1989, J PHARMACOL EXP THER, V249, P311
[10]   ETHANOL-INDUCED DISTURBANCE OF HEPATIC MICROCIRCULATION AND HEPATIC HYPOXIA [J].
HIJIOKA, T ;
SATO, N ;
MATSUMURA, T ;
YOSHIHARA, H ;
TAKEI, Y ;
FUKUI, H ;
OSHITA, M ;
KAWANO, S ;
KAMADA, T .
BIOCHEMICAL PHARMACOLOGY, 1991, 41 (11) :1551-1557