BACKGROUND & AIMS: Genetic variation of inosine triphosphatase (ITPA)causing an accumulation of inosine triphosphate (ITP) has been shown toprotect patients against ribavirin (RBV)-induced anemia during treatmentfor 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 adenylosuccinatesynthase (ADSS). RBV-induced adenosine triphosphate (ATP) reduction inerythrocytes was compared with the genetically determined low or normalactivity 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 guanosinetriphosphate (GTP). With RBV challenge, erythrocyte ATP reduction wasmore severe in the wild-type ITPA genotype than in the hemolysisprotective ITPA genotype. This difference also remains after inhibitingadenosine uptake using nitrobenzylmercaptopurine riboside (NBMPR).Interestingly, the alleviation of ATP reduction by the hemolysisprotective ITPA genotype was canceled by the ADSS inhibitor6-mercaptoethanol (6-MP). CONCLUSIONS: ITP confers protection againstRBV-induced ATP reduction by substituting for erythrocyte GTP, which isdepleted by RBV, in the biosynthesis of ATP. Because patients withexcess ITP appear largely protected against anemia, these resultsconfirm that RBV-induced anemia is due primarily to the effect of thedrug on GTP and consequently ATP levels in erythrocytes.