Martini R, Murray M
Department of Medicine, University of Sydney, Westmead Hospital, NSW, Australia.
Biochem Pharmacol. 1996 May 3;51(9):1187-93. doi: 10.1016/0006-2952(96)00054-8.
Microsomal aldehyde dehydrogenase (mALDH; EC 1.2.1.3) has been proposed to catalyze the oxidation of various aldehydic products of lipid peroxidation, but the regulation of the enzyme has not been characterized. Metyrapone administration (100 mg/kg, i.p.) produced a rapid decline in the rates of mALDH-catalyzed decanal dehydrogenation; other xenobiotics were generally without effect. Thus, a 22% decrease in activity was detected 2 hr following metyrapone administration, and 52% of the activity remained at 6 hr. The decrease in microsomal decanal dehydrogenation was also dose-dependent with 70, 43, and 12% of the control activity remaining following pretreatment with 25, 100, and 250 mg/kg metyrapone, respectively. This disease in microsomal decanal dehydrogenase activity occurred without a change in mALDH immunoreactive protein, and metyrapone did not inhibit the activity in vitro. The kinetic analysis revealed similar decreases in the maximal reaction velocities (Vmax) for both decanal and NAD in the metyrapone-treated group (200 +/- 10 and 190 +/- 20 nmol NADH produced/min/mg protein, respectively) compared with the untreated group (330 +/- 10 and 350 +/- 20 nmol NADH produced/min/mg protein, respectively), but the Michaelis constants (Km) were unchanged. These data are consistent with the in vivo inactivation of a portion of the mALDH enzyme. A possible consequence of the in vivo inhibition of this enzyme by metyrapone could be the accumulation of toxic aldehydes in the vicinity of the microsomal membrane following lipid peroxidation.
微粒体醛脱氢酶（mALDH；EC 1.2.1.3）被认为可催化脂质过氧化产生的各种醛类产物的氧化反应，但该酶的调节机制尚未明确。给予甲吡酮（100 mg/kg，腹腔注射）会使mALDH催化的癸醛脱氢反应速率迅速下降；其他外源化学物通常无此作用。因此，在给予甲吡酮2小时后，活性检测到下降了22%，6小时时仍保留52%的活性。微粒体癸醛脱氢反应的下降也呈剂量依赖性，分别用25、100和250 mg/kg甲吡酮预处理后，对照活性分别保留70%、43%和12%。微粒体癸醛脱氢酶活性的这种变化并未伴随mALDH免疫反应性蛋白的改变，且甲吡酮在体外不抑制该活性。动力学分析显示，与未处理组（分别为330±10和350±20 nmol NADH产生/分钟/毫克蛋白）相比，甲吡酮处理组中癸醛和NAD的最大反应速度（Vmax）均有类似程度的下降（分别为200±10和190±20 nmol NADH产生/分钟/毫克蛋白），但米氏常数（Km）未变。这些数据与部分mALDH酶在体内失活一致。甲吡酮在体内抑制该酶的一个可能后果是脂质过氧化后微粒体膜附近有毒醛类的蓄积。
