Human thiopurine S-methyltransferase activity in uremia and after renal transplantation.
In addition to cyclosporin and steroids, azathioprine is frequently used for immunosuppression after renal transplantation. Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs. A genetic polymorphism was shown with 1 in 300 homozygous for a TPMT deficiency. These subjects carry the risk of severe myelosuppression when treated with azathioprine.


OBJECTIVE
To investigate the influence of hemodialysis on TPMP activity in uremic patients and the effect of azathioprine treatment on enzyme activity.


METHODS
The assay for measurement of TPMT activity in packed red blood cells is based on a non-radioactive conversion of 6-thioguanine to 6-methylthioguanine. In 251 patients, TPMT activity was determined before and after a 4-h period of hemodialysis. In 49 patients (26 on azathioprine, 23 on mycophenolate mofetil as control group), TPMT activity was regularly determined during the first 120 days after renal transplantation.


RESULTS
TPMT activity is elevated in red blood cells of uremic patients before hemodialysis when compared with TPMT activity after hemodialysis. The latter is comparable to the activity in healthy subjects. In patients treated with azathioprine, the TPMT activity showed a slow increase that declined to pre-treatment values when azathioprine was withdrawn. This could not be observed in patients treated with mycophenolate mofetil.


CONCLUSIONS
In uremic patients, TPMT activity is activated by some uremic factors that are removed by hemodialysis. In contrast to what has been observed before, dialysis shifted the TPMT activity close to that of a healthy control group. In patients treated with azathioprine after renal transplantation, the observed increase of TPMT activity could possibly be the result of enzyme induction.
Weyer
N
N
Department of Experimental and Clinical Pharmacology and Toxicology, Luebeck Medical University, Ratzeburger Allee 160, 23538 Luebeck, Germany.
Kröplin
T
T
Fricke
L
L
Iven
H
H
D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008780:Methyltransferases / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D006435:Renal Dialysis; D014511:Uremia / Q000201:enzymology* / Q000628:therapy; D014850:Waiting Lists
D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine