AZATHIOPRINE HAEMATOTOXICITY DUE TO LOW T HIOPURINE METHYLTRANSFERASEACTIVITY AND XANTHINE-OXIDASE DEFICIENCY IN A RENAL-TRANSPLANTATION PATIENT

Azathioprine is an immunosuppressor used with ciclosporin and corticos teroids after organ transplantation. Azathioprine is rapidly transform ed into 6-mercaptopurine which in turn is metabolized by three competi tive pathways: a) intracellular hypoxanthine guanine phosphoribosyl tr ansferase leads to 6-thioguanine nucleotides which can damage chromoso me DNA; b) thiopurine methyltransferase produces inactive methylated d erivatives; c) xanthine oxidase produces thiouric acid. Due to interin dividual variations in the later two pathways, azathioprine dose must be adapted to each patient. A 48-year-old female patient underwent ren al transplantation in 1994 and was given immunosuppressive therapy com bining thymoglobulins, azathioprine and ciclosporin. Severe leukopenia (< 3000/mm(3) occurred on day 5 requiring withdrawal of azathioprine. , Known hypouricaemia (< 50 mu mol/l) suggested xanthine oxidase defic iency. Laboratory results confirmed xanthine oxidase deficiency and al so revealed reduced thiopurine methyltransferase activity (14.9 pmol/h /mg Hb). Azathioprine toxicity was confirmed by regression of the leuk openia after withdrawal and recurrence at rechallenge. Xanthine oxidas e deficiency occurs in 2% of the general population. Reduced thiopurin e methyltransferase activity affects 11% of the population, The combin ed presence of these two genetic anomalies led to early and sudden int olerance to azathioprine and emphasize the need to develop new Immunos uppressor agents degradated by other metabolic pathways.