Thiopurine methyltransferase gene polymorphisms and activity in Chinese patients with inflammatory bowel disease treated with azathioprine.
BACKGROUND
The thiopurine drugs are well established in the treatment of inflammatory bowel disease (IBD). However, uncertainty regarding the risk for neutropenia and hepatotoxicity deters its using. Thiopurine methyltransferase (TPMT) is the key enzyme in the metabolism of thiopurine. The aim of this study was to investigate the association of TPMT polymorphisms and activity with azathioprine (AZA)-related adverse events and clinical efficacy in Chinese Han patients with IBD.


METHODS
Fifty-two Han IBD patients treated with AZA were assessed for TPMT 2, 3A, 3B, and 3C, and for adverse events. Then, using reverse-phase high-performance liquid chromatography, TPMT activity was measured in 13 patients to analyze its correlation with AZA-related toxicity and clinical efficacy.


RESULTS
Of the 52 patients, five experienced myelotoxicity and one experienced hepatotoxicity during treatment. No TPMT 2, 3A, 3B or 3C polymorphisms were detected in any of the 52 patients. In the 13 patients with TPMT activity measurement, TPMT activity ranged from 7.2 to 28.8 U/ml packed red blood cells (pRBCs). Among the 5 patients who suffered from myelotoxicity, 3 were affected in the early stage of AZA therapy. In these 3 patients, TPMT levels were significantly lower than those in patients without myelotoxicity, which reached statistical significance ((9.3 ± 2.1) U/ml pRBC vs. (18.0 ± 6.2) U/ml pRBC; P = 0.046). One patient who had higher TPMT activity (28.8 U/ml pRBC) suffered from hepatotoxicity during AZA therapy. Patients who achieved a clinical response had lower TPMT activity than those failed to respond ((13.7 ± 3.5) U/ml pRBC vs. (22.0 ± 5.5) U/ml pRBC; P = 0.009).


CONCLUSIONS
TPMT variants do not completely account for the AZA-related myelotoxicity in Chinese Han IBD patients. However, measurement of TPMT activity may be helpful in reducing the risk of toxicity, and predicting the therapeutic efficacy.
Department of Gastroenterology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, China.
Qin
Q
Zhu
Qian
Q
Cao
D000293:Adolescent; D000328:Adult; D000368:Aged; D000963:Antimetabolites / Q000627:therapeutic use*; D001379:Azathioprine / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011110:Polymorphism, Genetic
D000963:Antimetabolites; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine