Red blood cell hypoxanthine phosphoribosyltransferase activity measured using 6‐mercaptopurine as a substrate: a population study in children with acute lymphoblastic leukaemia

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Abstract
6‐Mercaptopurine (6‐MP) is used in the continuing chemotherapy of childhood acute lymphoblastic leukaemia. The formation of red blood cell (RBC) 6‐thioguanine nucleotide (6‐TGN) active metabolites, not the dose of 6‐MP, is related to cytotoxicity and prognosis. But there is an apparent sex difference in 6‐MP metabolism. Boys require more 6‐MP than girls to produce the same range of 6‐TGN concentrations. Given the same dose, they experience fewer dose reductions because of cytotoxicity, and have a higher relapse rate. The enzyme hypoxanthine phosphoribosyltransferase (HPRT) catalyses the initial activation step in the metabolism of 6‐MP to 6‐TGNs, a step that requires endogenous phosphoribosyl pyrophosphate (PRPP) as a cosubstrate. Both HPRT and the enzyme responsible for the formation of PRPP are X‐linked. RBC HPRT activity was measured in two populations, 86 control children and 63 children with acute lymphoblastic leukaemia. 6‐MP was used as the substrate and the formation of the nucleotide product, 6‐thioinosinic acid (TIA) was measured. RBC 6‐TGN concentrations were measured in the leukaemic children at a standard dose of 6‐MP. There was a 1.3 to 1.7 fold range in HPRT activity when measured under optimal conditions. The leukaemic children had significantly higher HPRT activities than the controls (median difference 4.2 μmol TIA ml−1 RBCs h−1, 95% C.I. 3.7 to 4.7, P < 0.0001). In the leukaemic children HPRT activity (range 20.4 to 26.6 μmol TIA ml−1 RBCs h−1, median 23.6) was not related to the production of 6‐TGNs (range 60 to 1,024 pmol 8 × 10−8 RBCs, median 323). RBC HPRT was present at a high activity even in those children with low 6‐TGN concentrations. When HPRT is measured under optimal conditions it does not appear to be the metabolic step responsible for the observed sex difference in 6‐MP metabolism. This may be because RBC HPRT activity is not representative of other tissues but it could equally be because other sex‐linked factors are influencing substrate availability.