Pharmacogenetics of thiopurines in inflammatory bowel disease.
Thiopurines are widely used in the treatment of inflammatory bowel disease (IBD). However, in clinical practice azathioprine (AZA) or 6-mercaptopurine (6-MP) are not effective in one-third of patients and up to one-fifth of patients discontinue thiopurine therapy due to adverse reactions. The observed interindividual differences in therapeutic response and toxicity to thiopurines are explained to a large extent by the variable formation of active metabolites, which is at least partly caused by genetic polymorphisms of the genes encoding crucial enzymes in thiopurine metabolism. In this in-depth review we discuss the genetic polymorphisms of genes encoding for glutathione S-tranferases, xanthine oxidase, thiopurine S-methyltransferase, inosine triphosphate pyrophosphatase, hypoxanthine phosphoribosyltransferase, inosine monophosphate dehydrogenase and multidrug resistance proteins. Pharmacogenetic knowledge in this field has increased dramatically and is still rapidly increasing, but the translation into practical guidelines with tailored advices will cost much effort in the near future.
Derijks
Luc J J
LJ
Department of Clinical Pharmacy, Máxima Medical Centre, PO Box 7777, 5500 MB Veldhoven, The Netherlands. l.derijks@mmc.nl
Wong
Dennis R
DR
D018432:Drug Resistance, Multiple; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011687:Purines / Q000627:therapeutic use*; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism; D014969:Xanthine Oxidase / Q000235:genetics / Q000378:metabolism; D000097630:Inosine Triphosphatase
D005982:Glutathione Transferase; D007041:Hypoxanthine Phosphoribosyltransferase; D008780:Methyltransferases; D011687:Purines; D011755:Pyrophosphatases; D014969:Xanthine Oxidase; C022745:thiopurine methyltransferase; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase