Decaux G, Horsmans Y, Houssiau F, Desager J P
General Internal Medicine Department, University Hospital Erasme, Brussels, Belgium.
Am J Ther. 2001 May-Jun;8(3):147-50. doi: 10.1097/00045391-200105000-00002.
Azathioprine (AZA) is characterized by a high interindividual variability in bioavailability and metabolism. AZA is converted into 6-thioguanine nucleotides (6-TGN) to which the immune modifier activity is attributed. The 6-TGN levels are known to be affected by the activity of the key enzyme, thiopurine methyltransferase (TPMT), which is under genetic dependence. The authors measured a significantly lower TPMT activity in 53 women with systemic lupus erythematosus (SLE) (12.2 +/- 2.4 pmol/h/ml RBC; P < 0.01) when compared with 30 healthy control participants (13.15 +/- 3.1 pmol/h/ml RBC) but not with 28 patients with other dysimmune diseases (non-SLE; 13.0 +/- 3.0 pmol/h/ml RBC; P = 0.10). To evaluate the impact of TPMT activity on the concentrations of AZA metabolites, we measured the TPMT activity and 6-TGN levels in a subgroup of 26 patients in remission and treated with a stable dose of AZA (mean value: 1.9 +/- 0.5 mg/kg/day) for at least six months (n = 13 with SLE and n = 13 with other dysimmune diseases, ie, non-SLE). In such a subgroup, no correlation between 6-TGN levels and TPMT activity was observed. However, patients with SLE presented lower TPMT activity and higher 6-TGN levels (215 +/- 123 versus 140 +/- 75 pmol/8 x 10(8) RBC in non-SLE patients; P < 0.04). It must be noted that transient increase in 6-methylmercaptopurine levels (6-MMP), a putative toxic metabolite (up to 21.7 nmol/8 x 10(8) RBC), was more frequently observed in the non-SLE group (P < 0.01). Even if a relationship was observed between low TPMT activity and 6-TGN levels in SLE, its clinical impact appears to be limited as far as regular hematologic controls are performed.
硫唑嘌呤（AZA）的特点是生物利用度和代谢存在高度个体间差异。AZA会转化为6-硫鸟嘌呤核苷酸（6-TGN），其免疫调节活性即归因于此。已知6-TGN水平受关键酶硫嘌呤甲基转移酶（TPMT）的活性影响，而TPMT的活性受遗传因素制约。与30名健康对照参与者（13.15±3.1 pmol/h/ml红细胞）相比，作者测得53名系统性红斑狼疮（SLE）女性患者的TPMT活性显著更低（12.2±2.4 pmol/h/ml红细胞；P<0.01），但与28名患有其他免疫失调疾病（非SLE）的患者相比无差异（13.0±3.0 pmol/h/ml红细胞；P = 0.10）。为评估TPMT活性对AZA代谢物浓度的影响，我们在26名病情缓解且接受稳定剂量AZA（平均值：1.9±0.5 mg/kg/天）治疗至少六个月的患者亚组中（n = 13名SLE患者和n = 13名患有其他免疫失调疾病即非SLE的患者）测量了TPMT活性和6-TGN水平。在该亚组中，未观察到6-TGN水平与TPMT活性之间存在相关性。然而，SLE患者的TPMT活性较低，6-TGN水平较高（非SLE患者为140±75 pmol/8×10⁸红细胞，SLE患者为215±123 pmol/8×10⁸红细胞；P<0.04）。必须指出的是，在非SLE组中更频繁地观察到推定的有毒代谢物6-甲基巯基嘌呤水平（6-MMP）的短暂升高（高达21.7 nmol/8×10⁸红细胞）（P<0.01）。即使在SLE中观察到低TPMT活性与6-TGN水平之间存在关联，但只要进行常规血液学检查，其临床影响似乎有限。
