INHIBITION OF RAT HEPATIC MITOCHONDRIAL ALDEHYDE DEHYDROGENASE MEDIATED ACETALDEHYDE OXIDATION BY TRANS-4-HYDROXY-2-NONENAL
INHIBITION OF RAT HEPATIC MITOCHONDRIAL ALDEHYDE DEHYDROGENASE MEDIATED ACETALDEHYDE OXIDATION BY TRANS-4-HYDROXY-2-NONENAL
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DOI：
10.1002/hep.1840130420
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发表时间：
1991-04-01
期刊：
影响因子：
13.5
通讯作者：
PETERSEN, DR
中科院分区：
文献类型：
--
作者：
MITCHELL, DY;PETERSEN, DR
已证明乙醇的肝氧化引起细胞膜的过氧化，导致作为肝醛脱氢酶底物的醛的产生。 这是本研究的目的，以评估的脂质过氧化产物，反式-4-羟基-2-壬烯醛，和乙醛的高亲和力的线粒体醛脱氢酶，这是在乙醇衍生的乙醛的氧化的突出的重要性的共氧化。 实验进行了测定的动力学参数的未受抑制的乙醛和4-羟基壬烯醛氧化的半纯化的线粒体乙醛脱氢酶制备的雄性Sprague-Dawley大鼠肝脏。 在低底物浓度和线粒体乙醛脱氢酶的米氏常数乙醛的底物的酶的亲和力分别为25和10倍，比4-羟基壬烯醛。 将乙醛与生理相关浓度的4-羟基壬烯醛（0.25至5.0 μ mol/L）和线粒体醛脱氢酶共孵育，证明4-羟基壬烯醛是乙醛氧化的有效竞争性或混合型抑制剂，对于0.48 μ mol/L的ALDH氧化乙醛，Lineweaver-Burk图的斜率增加两倍所需的4-羟基壬烯醛浓度。 这项研究的结果表明，酒精性脂质过氧化产物，反式-4-羟基-2-壬烯醛，是一种有效的抑制剂肝乙醛氧化，并可能加强肝细胞毒性的乙醛提出的酒精性肝病的病因。
The hepatic oxidation of ethanol has been demonstrated to cause peroxidation of cellular membranes, resulting in the production of aldehydes that are substrates for hepatic aldehyde dehydrogenases. It was the purpose of this study to evaluate the cooxidation of the lipid peroxidation product, trans-4-hydroxy-2-nonenal, and acetaldehyde by high-affinity mitochondrial aldehyde dehydrogenase, which is of prominent importance in the oxidation of ethanol-derived acetaldehyde. Experiments were performed for determination of kinetic parameters for uninhibited acetaldehyde and 4-hydroxynonenal oxidation by semi-purified mitochondrial aldehyde dehydrogenase prepared from male Sprague-Dawley rat liver. The affinity of the enzyme for the substrate at low substrate concentrations and the Michaelis-Menten constant of mitochondrial aldehyde dehydrogenase for acetaldehyde were 25 and 10 times greater, respectively, than those determined for 4-hydroxynonenal. Coincubation of acetaldehyde with physiologically relevant concentrations of 4-hydroxynonenal (0.25 to 5.0-mu-mol/L) with mitochondrial aldehyde dehydrogenase demonstrated that 4-hydroxynonenal is a potent competitive or mixed-type inhibitor of acetaldehyde oxidation, with concentration of 4-hydroxynonenal required for a twofold increase in the slope of the Lineweaver-Burk plot for acetaldehyde oxidation by ALDH of 0.48-mu-mol/L. The results of this study suggest that the aldehydic lipid peroxidation product, trans-4-hydroxy-2-nonenal, is a potent inhibitor of hepatic acetaldehyde oxidation and may potentiate the hepatocellular toxicity of acetaldehyde proposed to be an etiological factor of alcoholic liver disease.