Significance of Acetaldehyde-Protein Adducts in Patients With Alcoholic Hepatitis

酒精性肝炎以酒精滥用引起的肝脏急性炎症性损害为特征，但酒精滥用导致肝脏炎症的机制尚不清楚。最近，化学惰性异物在肝脏中被代谢激活，与肝脏大分子结合从而导致肝脏损伤的概念被用来解释一些药物的肝脏毒性。众所周知，乙醛也是乙醇氧化的活性代谢物。因此，乙醛有可能与肝细胞大分子共价结合，从而改变肝细胞的结构和功能。为验证这一点，将乙醛(100uM)经SD大鼠门静脉灌流60min而不再循环，并用氚氰化钠测定体外灌流大鼠肝细胞中乙醛加合物的形成。在a…中发现可以检测到氚的掺入更多经十六醛处理的肝细胞。然后，为了检测乙醛处理的大鼠肝细胞的免疫反应，将酒精性肝炎患者的血清与分离的肝细胞孵育，并检测血清中抗加合物的抗体。结果：12例酒精性肝炎患者中有10例血清抗体阳性，而31例非酒精性肝病患者血清抗体均为阴性。为研究乙醛加合物对细胞毒T细胞的反应，将酒精性和非酒精性肝病患者的淋巴细胞与乙醛共同孵育，其中一部分作为刺激细胞，另一部分作为靶细胞，用铬标记。用刺激细胞激活的淋巴细胞与靶细胞培养，18例酒精性肝病患者中有5例检测到淋巴细胞杀伤活性。14例非酒精性肝病患者未发现细胞毒作用。所有这些结果表明，对乙醛-蛋白质加合物的淋巴细胞毒反应至少部分地在酒精滥用引起的炎症反应中起作用。较少

Alcoholic hepatitis is characterized by acute inflammatory lesion of the liver caused by alcohol abuse, but the mechanism by which alcohol abuse induces hepatic inflammation is not known. Recently, the concept that chemically inert foreign substances are metabolically activated in the liver, combine with hepatic macromolecules and thereby cause liver injury has been invoked to explain the hepatotoxicity of a number of drugs. It is well-known that acetaldehyde is also an active metabolite of alcogol (ethanol) oxidation. Thus, acetaldehyde is possible to covalently bind to hepatocellular macromoecules and thereby alter hepatocellular structure and function. To test this, acetaldehyde (100uM) was perfused through the portal vein of SD rats for 60 min without recirculation and the formation of acetaldehyde adducts to isolated hepatocytes of the perfused rats was determined in vitro using tritiated sodium cyanoborohydride. The incorporation of the tritium was found to be detectable in the a … More cetaldehyde-treated hepatocytes. Then, to test an immunological reaction against the acetaldehyde-treated rat hepatocytes, sera from patients with alcoholic hepatitis were incubated with the isolated hepatocytes and serum antibodies to the adducts were determined. As a result, serum antibodies were found to be positive in 10 of 12 patients with alcoholic hepatitis, whereas they were negative in all 31 patients with non-alcoholic liver disease. In order to study cytotoxic T-cell response to acetaldehyde adducts, lymphocytes taken from patients with alcoholic and non-alcoholic liver diseases were incubated with acetaldehyde, and one part was used as stimulator cells and another as target cells after labeled with Cr. When lymphocytes activated with the stimulator cells were cultured with the target cells, lymphocyte cytotoxicity was detected in 5 of 18 patients with alcoholic liver disease. The cytotoxicity was not found in 14 patients with non-alcoholic liver disease. All these results suggest that lymphocytotoxic response to acetaldehyde-protein adducts is, at least in part, play a role for the inflammatory reaction caused by alcohol abuse. Less