Thiopurine S-methyltransferase and inosine triphosphate pyrophosphohydrolase genes in Japanese patients with inflammatory bowel disease in whom adverse drug reactions were induced by azathioprine/6-mercaptopurine treatment.
BACKGROUND
The main cause of azathioprine (AZA)/6-mercaptopurine (6MP)-induced adverse reactions is a reduction in the activities of the metabolizing enzymes thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphohydrolase (ITPA). Adverse reactions develop at a high frequency in Japanese patients at half the dose required for European and American patients; however, the association with TPMT and ITPA gene polymorphisms in Japanese has not been fully investigated.


METHODS
Gene mutations of TPMT and ITPA, the major AZA/6-MP -metabolizing enzymes, were investigated retrospectively in 16 Japanese patients with inflammatory bowel disease (IBD) in whom AZA/6MP treatment induced adverse reactions.


RESULTS
The TPMT gene was found to have a wild-type sequence in all patients, but in the ITPA gene a mutation, 94C>A, was detected at a rate of 50% (8/16), with 83.3% (5/6) occurring in patients with acute bone marrow suppression and 75% (3/4) in those with agranulocytosis. The 94C>A allele frequency was 10 of 32 (0.313; 95% CI, 0.180-0.486). Adverse reactions developed earlier in patients with the 94C>A mutation. However, in half the patients, no gene polymorphism was noted.


CONCLUSIONS
It is suggested that the ITPA gene mutation is closely related to the adverse reactions of AZA/6-MP in Japanese patients, and screening for the mutant allele is useful for predicting the most serious adverse reactions, agranulocytosis and acute bone marrow suppression.
Uchiyama
Kan
K
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine (Kashiwa Hospital), 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567, Japan.
Nakamura
Makoto
M
Kubota
Takahiro
T
Yamane
Tateki
T
Fujise
Kiyotaka
K
Tajiri
Hisao
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D001379:Azathioprine / Q000009:adverse effects / Q000627:therapeutic use; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000235:genetics; D003424:Crohn Disease / Q000188:drug therapy / Q000235:genetics; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D007564:Japan; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D011755:Pyrophosphatases / Q000235:genetics*; D012189:Retrospective Studies; D055815:Young Adult; D000097630:Inosine Triphosphatase
D001379:Azathioprine; D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D008780:Methyltransferases; D011755:Pyrophosphatases; D000097630:Inosine Triphosphatase; C022745:thiopurine methyltransferase