急性酒精中毒对离体灌注大鼠肝脏糖异生及其激素反应性的影响。

Effects of acute alcohol intoxication on gluconeogenesis and its hormonal responsiveness in isolated, perfused rat liver.

作者信息

Deaciuc I V, D'Souza N B, Lang C H, Spitzer J J

机构信息

Department of Physiology, Louisiana State University Medical Center, New Orleans 70112.

出版信息

Biochem Pharmacol. 1992 Oct 20;44(8):1617-24. doi: 10.1016/0006-2952(92)90480-7.

DOI:10.1016/0006-2952(92)90480-7

PMID:1358076

Abstract

Rats were acutely administered ethanol as a primed constant infusion in order to produce sustained blood ethanol levels of 8-12 or 55-65 mM. At the end of ethanol infusion the livers were either freeze-clamped in vivo or isolated and perfused for metabolic studies. The rate of gluconeogenesis and its responsiveness to phenylephrine (10 microM), prostaglandin F2 alpha (5 microM) and glucagon (10 nM), as well as the redox state of the cytosolic NAD(+)-NADH system were assessed in livers isolated from acutely ethanol-treated rats, and subsequently perfused without ethanol. For liver clamped in vivo, high- but not low-ethanol treatment decreased the ATP content by 31% and slightly increased ADP and AMP content, resulting in a decreased energy charge (11%). Glutamate and aspartate content was also increased in high-dose ethanol-infused rats with no changes in malate and 2-oxoglutarate content. Gluconeogenesis with saturating concentrations of lactate (4 mM)+pyruvate (0.4 mM) was delayed in reaching a plateau in the livers of high-dose ethanol-treated rats and its response to all three stimulators was impaired. Low-dose ethanol treatment only decreased the liver response to phenylephrine. While the perfused livers of low-dose ethanol-treated rats displayed no changes in adenine nucleotide content, the livers of high-dose ethanol-treated rats had a decreased ATP (35%) and an increased AMP (77%) content, paralleled by a fall in the total adenine nucleotides (14%) and energy charge (14%). No differences were observed between the saline- and ethanol-treated rats with respect to malate-aspartate shuttle intermediate concentration in perfused livers. Also, the livers of high-, but not low-dose ethanol-treated rats had a more negative value of NAD(+)-NADH redox state as compared to the livers of control rats. The data suggest that acute ethanol intoxication produces changes in liver metabolism and its responsiveness to hormones/agonists that are demonstrable for at least 2 hr after isolation and perfusion of the liver.

摘要

大鼠通过初始恒速输注急性给予乙醇，以产生8 - 12或55 - 65 mM的持续血液乙醇水平。在乙醇输注结束时，肝脏要么在体内进行冷冻钳夹，要么分离并灌注以进行代谢研究。在从急性乙醇处理的大鼠分离并随后在无乙醇条件下灌注的肝脏中，评估糖异生速率及其对去氧肾上腺素（10 microM）、前列腺素F2α（5 microM）和胰高血糖素（10 nM）的反应性，以及胞质NAD(+) - NADH系统的氧化还原状态。对于在体内钳夹的肝脏，高剂量而非低剂量乙醇处理使ATP含量降低31%，并使ADP和AMP含量略有增加，导致能荷降低（11%）。高剂量乙醇输注大鼠的谷氨酸和天冬氨酸含量也增加，而苹果酸和2 - 氧代戊二酸含量无变化。在高剂量乙醇处理大鼠的肝脏中，用饱和浓度的乳酸（4 mM）+丙酮酸（0.4 mM）进行糖异生达到平台期的时间延迟，并且其对所有三种刺激物的反应受损。低剂量乙醇处理仅降低肝脏对去氧肾上腺素的反应。虽然低剂量乙醇处理大鼠的灌注肝脏中腺嘌呤核苷酸含量无变化，但高剂量乙醇处理大鼠的肝脏中ATP含量降低（35%），AMP含量增加（77%），同时总腺嘌呤核苷酸含量下降（14%），能荷下降（14%）。在灌注肝脏中，盐水处理和乙醇处理大鼠之间在苹果酸 - 天冬氨酸穿梭中间产物浓度方面未观察到差异。此外，与对照大鼠的肝脏相比，高剂量而非低剂量乙醇处理大鼠的肝脏具有更负的NAD(+) - NADH氧化还原状态值。数据表明，急性乙醇中毒会导致肝脏代谢及其对激素/激动剂的反应性发生变化，这些变化在肝脏分离和灌注后至少2小时内是可证明的。