苯乙双胍与豚鼠肝糖异生的抑制作用

Phenethylbiguanide and the inhibition of hepatic gluconeogenesis in the guinea pig.

作者信息

Ogata K, Jomain-Baum M, Hanson R W

出版信息

Biochem J. 1974 Oct;144(1):49-57. doi: 10.1042/bj1440049.

DOI:10.1042/bj1440049

PMID:4462575

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1168463/

Abstract

Phenethylbiguanide inhibits the synthesis of phosphoenolpyruvate from malate or 2-oxoglutarate by isolated guinea-pig liver mitochondria. This inhibition is time- and concentration-dependent, with the maximum decrease in the rate of phosphoenolpyruvate synthesis (80%) evident after 10min of incubation with 1mm-phenethylbiguanide. 2. The phosphorylation of ADP by these mitochondria is also inhibited at increasing concentrations of phenethylbiguanide and there is a progressive increase in AMP formation. Guinea-pig liver mitochondria are more sensitive to this inhibition in oxidative phosphorylation caused by phenethylbiguanide than are rat liver mitochondria. 3. Simultaneous measurements of O(2) consumption and ADP phosphorylation with guinea-pig liver mitochondria oxidizing malate plus glutamate in State 3 indicated that phenethylbiguanide at low concentrations (0.1mm) inhibits respiration at Site 1. At higher phenethylbiguanide concentrations Site 2 is also inhibited. 4. Gluconeogenesis from lactate, pyruvate, alanine and glycerol by isolated perfused guinea-pig liver is inhibited to various degrees by phenethylbiguanide. Alanine is the most sensitive to inhibition (60% inhibition of the maximum rate by 0.1mm-phenethylbiguanide), whereas glycerol is relatively insensitive (25% inhibition at 4mm). 5. Gluconeogenesis from lactate and pyruvate by perfused rat liver was also inhibited by phenethylbiguanide, but only at high concentrations (8mm). Unlike guinea-pig liver, the inhibitory effect of phenethylbiguanide on rat liver was reversible after the termination of phenethylbiguanide infusion. 6. The time-course of inhibition of gluconeogenesis from the various substrates used in this study indicated a time-dependency which was related in part to the concentration of infused phenethylbiguanidine. This time-course closely paralleled that noted for the inhibition by phenethylbiguanide of phosphoenolpyruvate synthesis in isolated guinea-pig liver mitochondria.

摘要

苯乙双胍可抑制豚鼠离体肝线粒体由苹果酸或2-氧代戊二酸合成磷酸烯醇丙酮酸。这种抑制作用具有时间和浓度依赖性，在与1mmol/L苯乙双胍孵育10分钟后，磷酸烯醇丙酮酸合成速率最大降幅达80%。2. 随着苯乙双胍浓度增加，这些线粒体中ADP的磷酸化也受到抑制，且AMP生成逐渐增加。豚鼠肝线粒体对苯乙双胍引起的这种氧化磷酸化抑制作用比大鼠肝线粒体更敏感。3. 用处于状态3的豚鼠肝线粒体氧化苹果酸加谷氨酸时，同时测量氧气消耗和ADP磷酸化，结果表明低浓度（0.1mmol/L）的苯乙双胍抑制位点1的呼吸作用。在苯乙双胍浓度较高时，位点2也受到抑制。4. 苯乙双胍不同程度地抑制豚鼠离体灌注肝脏由乳酸、丙酮酸、丙氨酸和甘油进行的糖异生。丙氨酸对抑制作用最敏感（0.1mmol/L苯乙双胍使最大速率抑制60%），而甘油相对不敏感（4mmol/L时抑制25%）。5. 苯乙双胍也抑制大鼠灌注肝脏由乳酸和丙酮酸进行的糖异生，但仅在高浓度（8mmol/L）时。与豚鼠肝脏不同，停止输注苯乙双胍后，其对大鼠肝脏的抑制作用是可逆的。6. 本研究中使用的各种底物糖异生抑制的时间进程表明存在时间依赖性，这部分与输注的苯乙双胍浓度有关。该时间进程与苯乙双胍对豚鼠离体肝线粒体中磷酸烯醇丙酮酸合成的抑制情况密切平行。