Elevation of erythrocyte redox potential linked to galactonate biosynthesis: Elimination by tolrestat
Elevation of erythrocyte redox potential linked to galactonate biosynthesis: Elimination by tolrestat
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DOI：
10.1016/s0026-0495(98)90317-1
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发表时间：
1998-11-01
影响因子：
9.8
通讯作者：
Segal, S
中科院分区：
文献类型：
--
作者：
Berry, GT;Wehrli, S;Segal, S
本文研究了正常人和半乳糖-L-磷酸尿苷酰转移酶(GALT)缺乏症患者红细胞半乳糖代谢的交替途径。在正常细胞和突变细胞中，微摩尔量的半乳糖酸随着时间的延长而线性积累，并且随着半乳糖浓度增加到25 mmol/L，半乳糖醇的浓度也不到半乳糖酸水平的1/3，而在半乳糖血症细胞中，半乳糖-L-磷酸的浓度与半乳糖浓度相当。伴随着这些半乳糖代谢物的形成，两种细胞中基于乳酸和丙酮酸测量的红细胞氧化还原电位增加了四倍。这是由于丙酮酸减少了60%到72%，乳酸增加了24%到26%。半乳糖氧化成半乳糖生成NADH，这是氧化还原状态增加的最可能的解释。醛糖还原酶抑制剂Tolrest at(新泽西州普林斯顿惠氏艾尔斯特研究公司)在70mU/L的浓度下，在不影响半乳糖-L-磷酸的情况下，抑制两种类型细胞中半乳糖和半乳糖醇的形成，并消除氧化还原电位的增加，这表明丙酮酸和乳酸水平恢复到半乳糖暴露之前的水平。功能正常的半乳糖途径是GALT缺乏症患者处理半乳糖的一条途径，但通过改变细胞的氧化还原电位，它也可能导致半乳糖毒性。版权所有(C)1998年，W.B.桑德斯公司。
Alternate pathways of galactose metabolism were explored in erythrocytes from normal subjects and patients with galactose-l-phosphate uridylyltransferase (GALT) deficiency incubated with galactose. Micromolar quantities of galactonate accumulated in both normal and mutant cells linearly with time up to 5 hours and with concentrations of galactose up to 25 mmol/L. Galactitol also was found at levels less than one third of the galactonate level, while galactose-l-phosphate concentrations comparable to those of galactonate were found in galactosemic cells. Concomitant with the formation of these galactose metabolites, the erythrocyte redox potential based on measurement of lactate and pyruvate increased fourfold in both cell types. This was due to a 60% to 72% decrease in pyruvate and a 24% to 26% increase in lactate. The oxidation of galactose to galactonate, which is known to generate NADH, is the most likely explanation for the increase in the redox state. The aldose reductase inhibitor (ARI), Tolrestat (Wyeth Ayerst Research, Princeton, NJ), at 70 mu mol/L inhibited the formation of both galactonate and galactitol in both cell types without affecting galactose-l-phosphate, and eliminated the increase in the redox potential as indicated by restoration of pyruvate and lactate levels to the levels obtained before exposure of the cells to galactose. A functioning galactonate pathway is a route of galactose disposal in patients with GALT deficiency, but by altering the cellular redox potential, it may also contribute to galactose toxicity. Copyright (C) 1998 by W.B. Saunders Company.