Altintas Engin, Sezgin Orhan
Division of Gastroenterology, School of Medicine, Mersin University, Zeytinli Bahce Cad. Eski Otogar Yani, 33079 Mersin, Turkey.
Med Hypotheses. 2004;63(5):834-7. doi: 10.1016/j.mehy.2004.03.031.
Objective is to speculate on the ribavirin induced anemia by inhibiting S-adenosylhomocysteine (SAH)-hydrolase activity. The major toxicity associated with the use of ribavirin is hemolytic anemia. This adverse effect has been ascribed to the accumulation of ribavirin triphosphate in the erythrocyte, which interferes with erythrocyte function. Ribavirin has been found to inhibit SAH-hydrolase activity in erythrocyte. SAH is further hydrolyzed to adenosine and homocysteine by SAH-hydrolase. The formation of S-adenosylmethionine (SAM) is then demethylated to SAH. SAH, the metabolite of SAM, on the other hand is a powerful inhibitor of methyltransferase enzymes, competing for the SAM binding site. A concurrent decrease in SAM and an increase in SAH levels would inhibit methylation of many tissue components including proteins, DNA, RNA, phospholipids and other small molecules. The enzyme protein carboxyl methyltransferase type II has been recently shown to play a crucial role in the repair of damaged proteins. SAM is the methyl donor of the reaction, and its demethylated product, SAH is the natural inhibitor of this reaction, as well as of most SAM-dependent methylations. The biological function of this transmethylation reaction is related to the repair or degradation of age-damaged proteins. Methyl ester formation in erythrocyte membrane proteins has been used as a marker reaction to tag these abnormal residues and to monitor their increase associated with erythrocyte ageing diseases. Liver disease is complicated by cholesterol deposition in hepatic and extrahepatic membranes. Erythrocyte membrane fluidity has been improved with the administration of SAM and correlated with the cholesterol/phospholipid ratio of the membranes. The levels of SAH-hydrolase activity were also found to undergo a sharp decrease with red cell ageing. The similarity of these alterations with certain morphofunctional characteristics of erythrocyte in some conditions as chronic renal failure, liver disease and hereditary spherocytosis makes it possible to hypothesize that the inhibition of SAH-hydrolase could constitute at least a part of ribavirin induced hemolytic anemia.
目的是通过抑制S-腺苷同型半胱氨酸（SAH）水解酶活性来推测利巴韦林诱导的贫血。使用利巴韦林相关的主要毒性是溶血性贫血。这种不良反应归因于三磷酸利巴韦林在红细胞中的积累，这会干扰红细胞功能。已发现利巴韦林可抑制红细胞中的SAH水解酶活性。SAH通过SAH水解酶进一步水解为腺苷和同型半胱氨酸。然后S-腺苷甲硫氨酸（SAM）的形成被去甲基化为SAH。另一方面，SAH作为SAM的代谢产物，是甲基转移酶的强力抑制剂，可竞争SAM结合位点。SAM的同时减少和SAH水平的增加会抑制包括蛋白质、DNA、RNA、磷脂和其他小分子在内的许多组织成分的甲基化。最近发现II型酶蛋白羧基甲基转移酶在受损蛋白的修复中起关键作用。SAM是该反应的甲基供体，其去甲基化产物SAH是该反应以及大多数依赖SAM的甲基化反应的天然抑制剂。这种转甲基反应的生物学功能与老化受损蛋白的修复或降解有关。红细胞膜蛋白中的甲酯形成已被用作标记反应，以标记这些异常残基并监测它们与红细胞衰老疾病相关的增加情况。肝脏疾病因肝内和肝外膜中胆固醇沉积而复杂化。给予SAM可改善红细胞膜流动性，且与膜的胆固醇/磷脂比率相关。还发现随着红细胞衰老，SAH水解酶活性水平急剧下降。这些变化与某些疾病如慢性肾衰竭、肝脏疾病和遗传性球形红细胞增多症中红细胞的某些形态功能特征的相似性使得有可能推测SAH水解酶的抑制可能至少是利巴韦林诱导的溶血性贫血的一部分原因。
