title: Inosine triphosphate protects against ribavirin-induced adenosine triphosphate loss by adenylosuccinate synthase function.
abstract: OBJECTIVE
  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.
authors.affiliation: Center for Human Genome Variation, School of Medicine, Duke University, Durham, North Carolina, USA.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hitomi
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Cirulli
authors.forename: Jacques
authors.initials: J
authors.lastname: Fellay
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Curtis E
authors.initials: CE
authors.lastname: Gumbs
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis / Q000378:metabolism; D000265:Adenylosuccinate Synthase / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000740:Anemia / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D000998:Antiviral Agents / Q000633:toxicity; D004789:Enzyme Activation / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects* / Q000201:enzymology; D014644:Genetic Variation; D005838:Genotype; D006160:Guanosine Triphosphate / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007293:Inosine Triphosphate / Q000494:pharmacology*; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism; D012254:Ribavirin / Q000633:toxicity*; D055815:Young Adult; D000097630:Inosine Triphosphatase
chemical_list: D000255:Adenosine Triphosphate; D000265:Adenylosuccinate Synthase; D000998:Antiviral Agents; D006160:Guanosine Triphosphate; D007293:Inosine Triphosphate; D011755:Pyrophosphatases; D012254:Ribavirin; D000097630:Inosine Triphosphatase