Human thiopurine methyltransferase activity varies with red blood cell age

Aims Inherited differences in thiopurine methyltransferase (TPMT) activity are all important factor in the wide interindividual variations observed in the clinical response to thiopurine chemotherapy. The ann of this study wa s to establish a population range for red blood cell (RBC) TPMT activity in children with acute lymphoblastic leukaemia (ALL) at disease diagnosis. An additional aim was to investigate factors that call influence TPMT activit y within the RBC. Methods Blood samples were collected from children with ALL at disease diag nosis, prior to any blood transfusions, as part of the nationwide UK MRC AL L97 therapeutic trial. RBC TPMT activity was measured by h.p.l.c. RBCs were age-fractionated on Percoll density gradients. Results Pretreatment blood samples were received from 570 children within 3 days of venepuncture. TPMT activities at disease diagnosis ranged from 1.6 to 23.6 units/ml RBCs (median 7.9) compared with 0.654-18.8 units (median 12.9), in 111 healthy control children (median difference 4.5 units, 95% CI 3.9, 5.1 units, P<0.001). A TPMT quality control sample, aliquots of which were assayed in 60 analytical runs over a 12 month period, contained a med ian of 11.98 units with a CV of 11.6% Seven children had their RBCs age-fra ctionated on density gradients. TPMT activities in the top gradient (young cells) ranged from 4.2 to 14.1 units (median 7.5) and in the bottom gradien t (old cells) 1.5-12.6 units (median 4.7 units), median difference 2.3 unit s, 95% CI 0.7, 4.1, P=0.035. Conclusions Circulating RBCs do not constitute a homogeneous population. Th ey have a life span of around 120 days and during that time undergo a progr essive ageing process. The anaemia of ALL is due to deficient RBC productio n. The results of this Study indicate that PBC TPMT activities are signific antly lower in children with ALL at disease diagnosis. This may be due, at least in part, to a relative excess of older RBCs.