Diehl A M, Wells M, Brown N D, Thorgeirsson S S, Steer C J
Department of Medicine, Veterans Administration Medical Center, Washington, DC 20422.
J Clin Invest. 1990 Feb;85(2):385-90. doi: 10.1172/JCI114450.
Ethanol consumption retards the hepatic regenerative response to injury. This may contribute to the pathogenesis of liver injury in alcoholic individuals. The mechanisms responsible for ethanol-associated inhibition of liver regeneration are poorly understood. To determine if the antiregenerative effects of ethanol involve modulation of polyamine metabolism, parameters of polyamine synthesis were compared before and during surgically induced liver regeneration in ethanol-fed rats and isocalorically maintained controls. After partial hepatectomy, induction of the activity of ornithine decarboxylase (ODC), the rate limiting enzyme for polyamine synthesis, was delayed in rats that had been fed ethanol. This was correlated with reduced levels of putrescine, ODC's immediate product. Increases in hepatic spermidine and spermine were also inhibited. Differences in ODC activity between ethanol-fed and control rats could not be explained by differences in the expression of ODC mRNA or by differences in ODC apoenzyme concentrations, suggesting that chronic ethanol intake inactivates ODC posttranslationally. Supplemental putrescine, administered at partial hepatectomy and 4 and 8 h thereafter, increased hepatic putrescine concentrations and markedly improved DNA synthesis and liver regeneration in ethanol-fed rats. These data suggest that altered polyamine metabolism may contribute to the inhibition of liver regeneration that occurs after chronic exposure to ethanol.
乙醇摄入会延缓肝脏对损伤的再生反应。这可能是导致酒精性肝病患者肝损伤发病机制的一个因素。目前对乙醇相关的肝脏再生抑制机制了解甚少。为了确定乙醇的抗再生作用是否涉及多胺代谢的调节，我们比较了乙醇喂养大鼠和等热量维持对照组在手术诱导肝脏再生前后的多胺合成参数。部分肝切除术后，乙醇喂养的大鼠中，多胺合成的限速酶鸟氨酸脱羧酶（ODC）的活性诱导延迟。这与ODC的直接产物腐胺水平降低相关。肝脏中精胺和亚精胺的增加也受到抑制。乙醇喂养大鼠和对照大鼠之间ODC活性的差异不能用ODC mRNA表达的差异或ODC脱辅基酶浓度的差异来解释，这表明长期摄入乙醇会在翻译后使ODC失活。在部分肝切除时及之后4小时和8小时给予补充腐胺，可提高乙醇喂养大鼠肝脏中的腐胺浓度，并显著改善DNA合成和肝脏再生。这些数据表明，多胺代谢改变可能是长期接触乙醇后肝脏再生受到抑制的原因之一。
