title: [Hematotoxicity caused by azathioprine genetically determined and aggravated by xanthine oxidase deficiency in a patient following renal transplantation].
abstract: Azathioprine is an immunosuppressor used with ciclosporin and corticosteroids after organ transplantation. Azathioprine is rapidly transformed into 6-mercaptopurine which in turn is metabolized by three competitive pathways: a) intracellular hypoxanthine guanine phosphoribosyl transferase leads to 6-thioguanine nucleotides which can damage chromosome DNA; b) thiopurine methyltransferase produces inactive methylated derivatives; c) xanthine oxidase produces thiouric acid. Due to inter-individual variations in the later two pathways, azathioprine dose must be adapted to each patient. A 48-year-old female patient underwent renal transplantation in 1994 and was given immunosuppressive therapy combining thymoglobulins, azathioprine and ciclosporin. Severe leukopenia (< 3000/mm3) occurred on day 5 requiring withdrawal of azathioprine. Known hypouricaemia (< 50 mumol/l) suggested xanthine oxidase deficiency. Laboratory results confirmed xanthine oxidase deficiency and also revealed reduced thiopurine methyltransferase activity (14.9 pmol/h/mg Hb). Azathioprine toxicity was confirmed by regression of the leukopenia after withdrawal and recurrence at rechallenge. Xanthine oxidase deficiency occurs in 2% of the general population. Reduced thiopurine methyltransferase activity affects 11% of the population. The combined presence of these two genetic anomalies led to early and sudden intolerance to azathioprine and emphasize the need to develop new immunosuppressor agents degraded by other metabolic pathways.
authors.affiliation: Laboratoire de Pharmacologie, CHU de Besançon.
authors.forename: F
authors.initials: F
authors.lastname: Serre-Debeauvais
authors.forename: F
authors.initials: F
authors.lastname: Bayle
authors.forename: M
authors.initials: M
authors.lastname: Amirou
authors.forename: Y
authors.initials: Y
authors.lastname: Bechtel
authors.forename: C
authors.initials: C
authors.lastname: Boujet
authors.forename: P
authors.initials: P
authors.lastname: Vialtel
authors.forename: G
authors.initials: G
authors.lastname: Bessard
mesh_terms: D001379:Azathioprine / Q000627:therapeutic use / Q000633:toxicity*; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007674:Kidney Diseases / Q000188:drug therapy* / Q000601:surgery; D016030:Kidney Transplantation / Q000379:methods*; D007970:Leukopenia / Q000139:chemically induced*; D008875:Middle Aged; D011183:Postoperative Complications; D014969:Xanthine Oxidase / Q000172:deficiency*
chemical_list: D014969:Xanthine Oxidase; D001379:Azathioprine
vernacular_title: Hématotoxicité de l'azathioprine à déterminisme génétique aggravée par un déficit en xanthine oxydase chez une transplantée rénale.