Studies on methanol toxicity and formate metabolism in isolated hepatocytes. The role of methionine in folate-dependent reactions.
Studies on methanol toxicity and formate metabolism in isolated hepatocytes. The role of methionine in folate-dependent reactions.
复制标题
离体肝细胞中甲醇毒性和甲酸代谢的研究。
DOI：
10.1016/0006-2952(79)90598-7
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发表时间：
1979
影响因子：
5.8
通讯作者：
T. Tephly
中科院分区：
文献类型：
--
作者：
R. Billings;T. Tephly
在给猴子注射甲醇后，甲酸盐会积累并产生明显的代谢性酸中毒和眼部毒性。甲酸盐不会在大鼠体内蓄积，这是一种对甲醇毒性不敏感的物种。当分离的大鼠肝细胞与甲醇孵育时，甲醇氧化成二氧化碳的速率比在体内观察到的氧化速率要慢。此外，体内甲酸的积累类似于猴子体内的甲酸积累。在分离的肝细胞中，介导甲醇氧化成甲醛、甲酸盐和二氧化碳的酶与报道的类似。因此，甲酸盐通过叶酸依赖的反应被氧化成二氧化碳。在含有甲醇的肝细胞孵育中加入蛋氨酸，通过促进甲酸盐的氧化，提高了甲醇氧化为二氧化碳的速率。因此，在分离的肝细胞中，甲酸在甲醇氧化过程中的积累是由于蛋氨酸缺乏导致明显的功能性叶酸缺乏导致甲酸盐氧化为二氧化碳的速度减慢。蛋氨酸在甲酸氧化为二氧化碳中的重要性在从叶酸缺乏的大鼠获得的肝细胞制剂中也很明显。在这些肝细胞中。单独添加5-甲酰基四氢叶酸对恢复甲酸盐氧化没有效果，但与蛋氨酸一起添加时有效。分离的肝细胞可能是一个有用的模型来研究参与调节甲醇到二氧化碳代谢的因素，因为它可以调节甲醇氧化到二氧化碳途径中的每一步。
Following the administration of methanol to monkeys, formate accumulates and produces a marked metabolic acidosis and ocular toxicity. Formate does not accumulate in the rat, a species not sensitive to methanol toxicity. When isolated rat hepatocytes were incubated with methanol, the rate of methanol oxidation to carbon dioxide was reduced compared to the rate of oxidation observed in the ratin vivo. Furthermore, there was an accumulation of formate similar to that seen in the monkeyin vivo. The enzymes in isolated hepatocytes which mediate methanol oxidation to formaldehyde, formate and carbon dioxide are similar to those reported for the ratin vivo. Thus, formate is oxidized to carbon dioxide by folate-dependent reactions. The addition of methionine to hepatocyte incubations containing methanol enhanced the oxidation rate of methanol to carbon dioxide by stimulating the oxidation of formate. Thus, in isolated hepatocytes the accumulation of formate during methanol oxidation was due to the development of a methionine deficiency which produced an apparent functional folate deficiency leading to a reduction in the rate of oxidation of formate to carbon dioxide. The importance of methionine in formate oxidation to carbon dioxide is also apparent in hepatocyte preparations obtained from folate-deficient rats. In these hepatocytes. the addition of 5-formyltetrahydrofolate alone was ineffective in restoring formate oxidation, but it was effective when methionine was also added. Isolated hepatocytes may be a useful model for studying the factors involved in regulating the metabolism of methanol to carbon dioxide, since it is possible to regulate each step in the pathway of methanol oxidation to carbon dioxide.