Inosine Triphosphate Protects Against Ribavirin-Induced Adenosine Triphosphate Loss by Adenylosuccinate Synthase Function
Inosine Triphosphate Protects Against Ribavirin-Induced Adenosine Triphosphate Loss by Adenylosuccinate Synthase Function
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DOI：
10.1053/j.gastro.2010.12.038
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发表时间：
2011-04-01
期刊：
影响因子：
29.4
通讯作者：
Goldstein, David B.
中科院分区：
文献类型：
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作者：
Hitomi, Yuki;Cirulli, Elizabeth T.;Goldstein, David B.
背景与目的：全基因组关联研究（GWAS）显示，导致肌苷三磷酸酶（ITP）蓄积的肌苷三磷酸酶（ITPA）遗传变异可保护患者在治疗慢性丙型肝炎感染期间免受利巴韦林（RBV）诱导的贫血。然而，这种情况发生的生物学机制尚不清楚。方法：我们研究了ITP是否可以被人红细胞中的腺苷三磷酸酶（ATP酶）或重组人腺苷琥珀酸合酶（ADSS）所利用。将RBV诱导的红细胞中三磷酸腺苷（ATP）减少与遗传确定的ITPA低或正常活性进行比较，分别导致高或正常ITP水平。研究结果：虽然ITP不直接被人红细胞ATP酶使用，但它可以通过ADSS代替三磷酸鸟苷（GTP）用于ATP生物合成。与RBV挑战，红细胞ATP减少是更严重的野生型ITPA基因型比溶血保护ITPA基因型。在使用硝基苄基巯基嘌呤核苷（NBMPR）抑制腺苷摄取后，这种差异也仍然存在。有趣的是，溶血保护ITPA基因型对ATP减少的缓解被ADSS抑制剂6-巯基乙醇（6-MP）抵消。结论：ITP通过在ATP的生物合成中取代被RBV耗尽的红细胞GTP来提供针对RBV诱导的ATP减少的保护。由于ITP过多的患者似乎在很大程度上免受贫血的影响，这些结果证实RBV诱导的贫血主要是由于药物对红细胞中GTP和ATP水平的影响。
BACKGROUND & AIMS: Genetic variation of inosine triphosphatase (ITPA) causing an accumulation of inosine triphosphate (ITP) has been shown to protect patients against ribavirin (RBV)-induced anemia during treatment for chronic hepatitis C infection by genome-wide association study (GWAS). However, the biologic mechanism by which this occurs is unknown. METHODS: We examined whether ITP can be used by adenosine triphosphatase (ATPase) in human erythrocytes or recombinant human adenylosuccinate synthase (ADSS). RBV-induced adenosine triphosphate (ATP) reduction in erythrocytes was compared with the genetically determined low or normal activity of ITPA, leading respectively to high or normal ITP levels. RESULTS: Although ITP is not used directly by human erythrocyte ATPase, it can be used for ATP biosynthesis via ADSS in place of guanosine triphosphate (GTP). With RBV challenge, erythrocyte ATP reduction was more severe in the wild-type ITPA genotype than in the hemolysis protective ITPA genotype. This difference also remains after inhibiting adenosine uptake using nitrobenzylmercaptopurine riboside (NBMPR). Interestingly, the alleviation of ATP reduction by the hemolysis protective ITPA genotype was canceled by the ADSS inhibitor 6-mercaptoethanol (6-MP). CONCLUSIONS: ITP confers protection against RBV-induced ATP reduction by substituting for erythrocyte GTP, which is depleted by RBV, in the biosynthesis of ATP. Because patients with excess ITP appear largely protected against anemia, these results confirm that RBV-induced anemia is due primarily to the effect of the drug on GTP and consequently ATP levels in erythrocytes.