Relationships between thiopurine S-methyltransferase polymorphism and azathioprine-related adverse drug reactions in Chinese renal transplant recipients.
OBJECTIVE
To systematically investigate the relationships between thiopurine S-methyltransferase (TPMT) polymorphisms and azathioprine-related adverse drug reactions in patients with kidney transplantation.


METHODS
Erythrocyte TPMT activity of 150 patients with kidney transplantation and AZA therapy was determined by HPLC. The frequency of four common TPMT mutant alleles, TPMT*2, *3A, *3B, and *3C was determined by allele-specific PCR and PCR-restriction fragment length polymorphism (PCR-RFLP) analysis.


RESULTS
Thirty cases (20%) had stopped azathioprine medication or were on reduced dose due to azathioprine-related side effects. The TPMT activity range of cases who never experienced side effects was 16.63-68.25 U, the mean of the controls was 38.43 +/- 11.59 U. The mean value of 12 cases with hematotoxicity was 23.50 +/- 10.33 U, much lower than the control mean (P < 0.05). No significant difference between the mean value of 18 cases with hepatotoxicity and the control mean (P > 0.05) was seen. No case with TPMT deficiency was found in all patients studied, and TPMT*2, *3A, and *3B were not detected in any of them. TPMT*3C heterozygous alleles were found in 4.7% (seven cases) of these patients, all seven cases had intermediate TPMT activity, and the mean was 16.75 +/- 2.09 U, much lower than other TPMT wild-type patients (P < 0.05). In the seven TPMT*3C patients, four cases experienced side effects (hematotoxicity, n = 2; hepatotoxicity, n = 2).


CONCLUSIONS
This study demonstrates that TPMT activity is reduced in patients with TPMT*3C mutation. AZA-induced hematotoxicity is related to the reduced TPMT activity.
Xin
Hua-Wen
HW
Department of Clinical Pharmacology, Wuhan General Hospital of Guangzhou Command, Wuhan 430070, PR China. huawenxin@163.com
Xiong
Hui
H
Wu
Xiao-Chun
XC
Li
Qing
Q
Xiong
Lei
L
Yu
Ai-Rong
AR
D000328:Adult; D000368:Aged; D044466:Asian People; D001379:Azathioprine / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D006084:Graft Rejection / Q000517:prevention & control; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic
D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine