Handler J A, Bradford B U, Glassman E B, Forman D T, Thurman R G
Department of Pharmacology, University of North Carolina, Chapel Hill 27514.
Biochem J. 1987 Dec 1;248(2):415-21. doi: 10.1042/bj2480415.
Hepatic microsomal fractions from ADH (alcohol dehydrogenase)-negative deermice incubated with an NADPH-generating system metabolized butanol and ethanol at rates around 10 nmol/min per mg. In contrast, cytosolic catalase from ADH-negative deermouse liver oxidized ethanol, but not butanol, when incubated with an H2O2-generating system. Thus butanol is oxidized by cytochrome P-450 in microsomal fractions, but not by cytosolic catalase, in tissues from ADH-negative deermice. In perfused livers from ADH-negative deermice, rates of ethanol uptake at low concentrations of ethanol (1.5 mM) were about 60 mumol/h per g, yet butanol (1.5 mM) uptake was undetectable (less than 4 mumol/h per g). At higher concentrations of alcohol (25-30 mM), rates of ethanol uptake were about 80 mumol/h per g, whereas rates of butanol uptake were only about 9 mumol/h per g. Because rates of butanol metabolism via cytochrome P-450 in deermice were more than an order of magnitude lower than rates of ethanol uptake in livers from ADH-negative deermice, it is concluded that ethanol uptake by perfused livers from ADH-negative deermice is catalysed predominantly via catalase-H2O2. In support of this conclusion, rates of H2O2 generation, which are rate-limiting for the peroxidation of ethanol by catalase, were about 65 mumol/h per g in livers from ADH-negative deermice, values similar to rates of ethanol uptake of about 60 mumol/h per g measured under identical conditions. Rates of ethanol uptake by perfused livers from ADH-positive, but not from ADH-negative, deermice were increased by about 50% by infusion of fructose. Thus it is concluded that the stimulation of hepatic ethanol uptake by fructose is dependent on the presence of ADH. Unexpectedly, fructose decreased rates of ethanol metabolism and H2O2 generation by about 60% in perfused livers from ADH-negative deermice, probably by decreasing activation of fatty acids and thus diminishing rates of peroxisomal beta-oxidation.
在与NADPH生成系统一起孵育时，来自抗乙醇脱氢酶（ADH）的鹿鼠的肝微粒体部分以约每毫克10纳摩尔/分钟的速率代谢丁醇和乙醇。相比之下，当与H2O2生成系统一起孵育时，来自抗ADH鹿鼠肝脏的胞质过氧化氢酶氧化乙醇，但不氧化丁醇。因此，在抗ADH鹿鼠的组织中，丁醇被微粒体部分中的细胞色素P - 450氧化，而不是被胞质过氧化氢酶氧化。在抗ADH鹿鼠的灌注肝脏中，低浓度乙醇（1.5 mM）时的乙醇摄取速率约为每克60微摩尔/小时，而丁醇（1.5 mM）摄取则检测不到（低于每克4微摩尔/小时）。在较高浓度的酒精（25 - 30 mM）下，乙醇摄取速率约为每克80微摩尔/小时，而丁醇摄取速率仅约为每克9微摩尔/小时。由于鹿鼠中通过细胞色素P - 450的丁醇代谢速率比抗ADH鹿鼠肝脏中乙醇摄取速率低一个数量级以上，因此得出结论，抗ADH鹿鼠的灌注肝脏对乙醇的摄取主要通过过氧化氢酶 - H2O2催化。支持这一结论的是，过氧化氢生成速率是过氧化氢酶对乙醇过氧化作用的限速因素，在抗ADH鹿鼠的肝脏中约为每克65微摩尔/小时，这一数值与在相同条件下测得的约每克60微摩尔/小时的乙醇摄取速率相似。灌注来自ADH阳性而非ADH阴性鹿鼠的肝脏时，通过注入果糖，乙醇摄取速率增加约50%。因此得出结论，果糖对肝脏乙醇摄取的刺激依赖于ADH的存在。出乎意料的是，果糖使抗ADH鹿鼠灌注肝脏中的乙醇代谢速率和H2O2生成速率降低约60%，可能是通过降低脂肪酸的活化从而降低过氧化物酶体β - 氧化速率。
