Azathioprine pharmacogenetics: the relationship between 6-thioguanine nucleotides and thiopurine methyltransferase in patients after heart and kidney transplantation.
The commonly used immunosuppressive regimen after solid organ transplantation consists of cyclosporine A, azathioprine and steroids. Azathioprine, which is known to carry the risk of severe myelosuppression, is catabolized in vivo by xanthine oxidase and thiopurine methyltransferase, an enzyme which exhibits a common genetic polymorphism; 11% of Caucasians are heterozygous and 0.3% are homozygous with respect to thiopurine methyltransferase deficiency. Toxicity and immunosuppressive effects have been attributed to the 6-thioguanine nucleotides generated from azathioprine. We have studied thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations in erythrocytes from 39 heart and kidney recipients. Erythrocyte thiopurine methyl-transferase was determined by a radioenzymatic assay and erythrocyte 6-thioguanine nucleotide concentration with HPLC. Thiopurine methyltransferase activity [median (range, 10th-90th percentile)] was significantly (p < 0.05) higher in patients (n = 39) receiving azathioprine [285 (218-362) vs. 262 (160-352) mU/I erythrocytes] than in healthy blood donors as controls (n = 120). When stratified according to thiopurine methyltransferase phenotype, one patient homozygous for the low allele exhibited an excessive erythrocyte 6-thioguanine nucleotide concentration (2210 pmol/0.8 x 10(9) erythrocytes). Heterozygous patients had significantly higher 6-thioguanine nucleotide concentrations median: 435 pmol/0.8 x 10(9) erythrocytes) compared with concentrations in patients homozygous for the high allele (median: 86 pmol/0.8 x 10(9) erythrocytes; p < 0.01), although the azathioprine dosage did not differ (p = 0.66). Erythrocyte thiopurine methyltransferase determination therefore identifies patients at high risk of accumulating 6-thioguanine nucleotides. The monitoring of this enzyme may contribute to the safer management of immunosuppressive therapy with azathioprine. Alternative regimens such as cyclosporin A/mycophenolate mofetil or tacrolimus should also be considered for this patient group.
Schütz
E
E
Abteilung Klinische Chemie, Georg-August-Universität Göttingen, Germany.
Gummert
J
J
Armstrong
V W
VW
Mohr
F W
FW
Oellerich
M
M
D001379:Azathioprine / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism; D004912:Erythrocytes / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006150:Guanine Nucleotides / Q000097:blood* / Q000378:metabolism; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology; D008297:Male; D008780:Methyltransferases / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011863:Radioimmunoassay; D013873:Thionucleotides / Q000097:blood* / Q000378:metabolism; D044465:White People / Q000235:genetics; D014969:Xanthine Oxidase / Q000235:genetics / Q000378:metabolism
D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; D004247:DNA; D014969:Xanthine Oxidase; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine