Center for Human Genome Variation, School of Medicine, Duke University, Durham, North Carolina, USA.
Gastroenterology. 2011 Apr;140(4):1314-21. doi: 10.1053/j.gastro.2010.12.038. Epub 2011 Jan 1.
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.
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.
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).
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.
通过全基因组关联研究（GWAS）发现，肌苷三磷酸酶（ITPA）的遗传变异导致肌苷三磷酸（ITP）积累，可保护慢性丙型肝炎感染患者在接受利巴韦林（RBV）治疗时免受 RBV 诱导的贫血。然而，其发生的生物学机制尚不清楚。
我们研究了 ITP 是否可被人红细胞的三磷酸腺苷酶（ATPase）或重组人腺嘌呤核苷酸琥珀酸合成酶（ADSS）利用。比较了 RBV 诱导的红细胞三磷酸腺苷（ATP）减少与 ITPA 低或正常活性的遗传决定因素，分别导致高或正常的 ITP 水平。
尽管 ITP 不能直接被人红细胞 ATPase 利用，但它可以通过 ADSS 用于替代鸟嘌呤三磷酸（GTP）合成 ATP。在 RBV 挑战下，野生型 ITPA 基因型的红细胞 ATP 减少比溶血保护型 ITPA 基因型更为严重。在用硝基苯甲基巯基嘌呤核糖核苷（NBMPR）抑制腺苷摄取后，这种差异仍然存在。有趣的是，溶血保护型 ITPA 基因型通过替代 RBV 耗尽的红细胞 GTP 来减轻 ATP 减少的作用被 ADSS 抑制剂 6-巯基乙醇（6-MP）取消。
ITP 通过替代 RBV 耗尽的红细胞 GTP 用于 ATP 的生物合成，从而对 RBV 诱导的 ATP 减少提供保护。由于过多的 ITP 似乎使患者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 GTP 及其随后对 ATP 水平的影响所致。
