乙醇对肝脏糖异生的抑制作用。

Inhibition of hepatic gluconeogenesis by ethanol.

作者信息

Krebs H A, Freedland R A, Hems R, Stubbs M

出版信息

Biochem J. 1969 Mar;112(1):117-24. doi: 10.1042/bj1120117.

DOI:10.1042/bj1120117

PMID:5774487

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1187647/

Abstract

Gluconeogenesis from 10mm-lactate in the perfused liver of starved rats is inhibited by ethanol. The degree of inhibition reached a maximum of 66% at 10mm-ethanol under the test conditions and decreased at higher ethanol concentrations. The concentration-dependence of the inhibition is paralleled by the concentration-dependence of the activity of alcohol dehydrogenase. The enzyme is also inhibited by ethanol concentrations above 10mm. 2. Gluconeogenesis from pyruvate is not inhibited by ethanol. 3. The degree of the inhibition of gluconeogenesis from lactate by ethanol depends on the concentration of lactate and other oxidizable substances, e.g. oleate, in the perfusion medium. 4. Ethanol also inhibits, to different degrees, gluconeogenesis from glycerol, dihydroxyacetone, proline, serine, alanine, fructose and galactose. 5. The inhibition of gluconeogenesis from lactate by ethanol is reversed by acetaldehyde. 6. Pyrazole, a specific inhibitor of alcohol dehydrogenase, also reverses the inhibition of gluconeogenesis by ethanol. 7. Gluconeogenesis in kidney cortex, where the activity of alcohol dehydrogenase is very low, is not inhibited by ethanol. 8. Kidney cortex, testis, ovary, uterus and certain tissues of the alimentary tract were the only rat tissues, apart from the liver, that showed measurable alcohol dehydrogenase activity. 9. The concentrations of pyruvate in the liver were decreased to about one-fifth by ethanol. 10. The concentration of lactate in the perfused liver was about 3mm below that of the perfusion medium 30min. after the addition of 10mm-lactate. 11. The great majority of the findings support the view that the inhibition of gluconeogensis by ethanol is caused by the alcohol dehydrogenase reaction, which decreases the [free NAD(+)]/[free NADH] ratio. The decrease lowers the concentration of pyruvate and this is the immediate cause of the inhibition of gluconeogenesis from lactate, alanine and serine: the fall in the concentration of pyruvate lowers the rate of the pyruvate carboxylase reaction, one of the rate-limiting reactions of gluconeogenesis. The cause of the inhibition of gluconeogenesis from other substrates is discussed.

摘要

在饥饿大鼠的灌注肝脏中，乙醇会抑制由10mmol/L乳酸生成葡萄糖的糖异生过程。在测试条件下，当乙醇浓度为10mmol/L时，抑制程度最高可达66%，而在更高的乙醇浓度下抑制程度会降低。这种抑制作用的浓度依赖性与乙醇脱氢酶活性的浓度依赖性平行。乙醇浓度高于10mmol/L时，该酶也会受到抑制。2. 乙醇不会抑制由丙酮酸生成葡萄糖的糖异生过程。3. 乙醇对由乳酸生成葡萄糖的糖异生过程的抑制程度取决于灌注介质中乳酸和其他可氧化物质（如油酸）的浓度。4. 乙醇还会不同程度地抑制由甘油、二羟基丙酮、脯氨酸、丝氨酸、丙氨酸、果糖和半乳糖生成葡萄糖的糖异生过程。5. 乙醛可逆转乙醇对由乳酸生成葡萄糖的糖异生过程的抑制作用。6. 吡唑，一种乙醇脱氢酶的特异性抑制剂，也能逆转乙醇对糖异生过程的抑制作用。7. 在肾皮质中，乙醇脱氢酶的活性非常低，由肾皮质生成葡萄糖的糖异生过程不会受到乙醇的抑制。8. 除肝脏外，肾皮质、睾丸、卵巢、子宫和消化道的某些组织是大鼠体内仅有的显示出可测量乙醇脱氢酶活性的组织。9. 乙醇可使肝脏中丙酮酸的浓度降低至约五分之一。10. 在添加10mmol/L乳酸30分钟后，灌注肝脏中乳酸的浓度比灌注介质中的浓度低约3mmol/L。11. 绝大多数研究结果支持这样一种观点，即乙醇对糖异生过程的抑制是由乙醇脱氢酶反应引起的，该反应会降低[游离NAD(+)]/[游离NADH]的比值。这种降低会降低丙酮酸的浓度，这是抑制由乳酸、丙氨酸和丝氨酸生成葡萄糖的糖异生过程的直接原因：丙酮酸浓度的下降会降低丙酮酸羧化酶反应的速率，而丙酮酸羧化酶反应是糖异生过程中的限速反应之一。文中还讨论了乙醇对由其他底物生成葡萄糖的糖异生过程的抑制原因。