ribavirin (RBV)-induced anemia:Genetic variation of inosine triphosphatase

Inosine triphosphate protects against ribavirin-induced ATP loss by restoring adenylosuccinate synthase function


Yuki Hitomi1, Elizabeth T. Cirulli1, Jacques Fellay1, John G. McHutchison2, Alexander J. Thompson2, Curtis E. Gumbs1, Kevin V. Shianna1, Thomas J. Urban1 and David B. Goldstein1, ,

1 Center for Human Genome Variation, School of Medicine, Duke University, Durham, North Carolina 27708, USA

2 Duke Clinical Research Institute and Division of Gastroenterology, School of Medicine, Division of Gastroenterology, Duke University, Durham, North Carolina 27705, USA

Received 27 August 2010; revised 9 November 2010; accepted 14 December 2010. Available online 1 January 2011.

Abstract
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 biological mechanism by which this occurs is unknown.

Methods:
We examined whether ITP can be used by adenosine triphosphatase (ATPase) in human erythrocyte or recombinant human adenylosuccinate synthase (ADSS). RBV-induced adenosine triphosphate (ATP) reduction in erythrocyte 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 wildtype ITPA genotype than in the hemolysis protective ITPA genotype. This difference also remains by 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 ribavirin, in the biosynthesis of ATP. Since 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 erythrocyte.

Keywords: genetic variation; hepatitis C; ribavirin; anemia