Pharmacogenetic Significance of Inosine Triphosphatase

Abstract

Inosine triphosphatase (ITPase) is the enzyme that catalyzes the conversion of inosine triphosphate (ITP) and deoxy-inosine triphosphate (dITP) to inosine monophosphate and deoxy-inosine monophosphate, respectively, thereby maintaining low intracellular concentrations of ITP and dITP. Individuals deficient in ITPase activity were first recognized over 30 years ago. For decades, no clinical significance could be attributed to this inborn error of metabolism whatsoever. In recent years, evidence has started to accumulate that polymorphisms in the gene encoding ITPase are associated with potentially severe adverse drug reactions towards the thiopurine drugs azathioprine and 6-mercaptopurine. The pharmacogenetic significance is presently being debated in the literature. However, the present state of knowledge is still insufficient to definitively determine the pharmacogenetic significance of ITPase. This article aims to review the current knowledge on the role of ITPase in thiopurine metabolism.

Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population

“…Inosine triphosphate pyrophosphatase (ITPA) is one of several enzymes whose job is to cleanse the nucleotide pool [117] . ITPase also acts as a "cleaning" enzyme by degrading other "rogue" purine nucleotides in cells, eg, endogenous deoxyinosine triphosphate (dITP) and deoxy-xanthosine triphosphate (dXTP) [106,118,119] .…”

Evolving Trends in the Hepatitis C Virus Molecular Epidemiology Studies: From the Viral Sequences to the Human Genome

“…The association was explained by two known functional variants in the ITPA gene, located on chromosome 20 and encoding for inosine triphosphatase (ITPase). The two variants, a missense polymorphism in exon 2 (g.3141842C>A, P32T; rs1127354) and a splicealtering SNP located in the second intron (g.8838A>C, rs7270101), result in reduced enzyme activity: homozygosity for the P32T mutation leads to undetectable ITPase activity, accumulation of its substrate ITP in erythrocytes, and increased toxicity of purine analogue drugs [125,[127][128][129][130][131]. Conversely, reduced ITPase activity may be protective from RBV-induced hemolysis through the competition of ITP with RBV-TP [127,132].…”

A role for ITPA variants in the clinical course of pulmonary Langerhans' cell histiocytosis?

“…The role of ITPase in mammalian metabolism is still poorly understood [8]. Its primary role is the pyrophosphohydrolysis of ITP (and deoxy-ITP) to maintain the balance between ITP and inosine monophosphate (IMP), IMP being the key metabolite in the purine interconversion pathway.…”