AZATHIOPRINE PHARMACOGENETICS - THE RELATIONSHIP BETWEEN 6-THIOGUANINE NUCLEOTIDES AND THIOPURINE METHYLTRANSFERASE IN PATIENTS AFTER HEARTAND KIDNEY-TRANSPLANTATION

The commonly used immunosuppressive regimen after solid organ transpla ntation consists of cyclo-sporine A, azathioprine and steroids. Azathi oprine, which is known to carry the risk of severe myelosuppression, i s catabolized in vivo by xanthine oxidase and thiopurine methyltransfe rase, an enzyme which exhibits a common genetic polymorphism; 11% of C aucasians are heterozygous and 0.3% are homozygous with respect to thi opurine methyltransferase deficiency. Toxicity and immunosuppressive e ffects have been attributed to the 6-thioguanine nucleotides generated from azathioprine. We have studied thiopurine methyltransferase activ ity and 6-thioguanine nucleotide concentrations in erythrocytes from 3 9 heart and kidney recipients. Erythrocyte thiopurine methyltransferas e was determined by a radioenzymatic assay and erythrocyte B-thioguani ne nucleotide concentration with HPLC. Thiopurine methyltransferase ac tivity [median (range, 10(th)-90(th) 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 methyl transferase phenotype, one patient homozygous for the low allele exhib ited an excessive erythrocyte 6-thioguanine nucleotide concentration ( 2210 pmol/0.8 . 10(9) erythrocytes). Heterozygous patients had signifi cantly higher 6-thioguanine nucleotide concentrations (median: 435 pmo l/0.8 . 10(9) erythrocytes) compared with concentrations in patients h omozygous for the high allele (median: 86 pmol/0.8 . 10(9) erythrocyte s; p < 0.01), although the azathioprine dosage did not differ (p = 0.6 6). Erythrocyte thiopurine methyltransferase determination therefore i dentifies patients at high risk of accumulating 6-thioguanine nucleoti des. The monitoring of this enzyme mag. contribute to the safer manage ment of immunosuppressive therapy with azathioprine. Alternative regim ens such as cyclosporin A/mycophenolate mofetil or tacrolimus should a lso be considered for this patient group.