RESUMEN
Thiopurine methyltransferase (TPMT) catalyzes thiopurine S-methylation, an important metabolic pathway for drugs such as 6-mercaptopurine. Thiol methyltranferase (TMT) catalyzes the S-methylation of a variety of aliphatic sulfhydryl compounds. Erythrocyte (RBC) TPMT activity is elevated in the blood of uremic patients on maintenance hemodialysis, 15.83 +/- 0.90 U/ml RBCs (mean +/- SEM, n = 41), whereas in blood from randomly seleted nonuremic subjects it was 12.76 +/- 0.16 U/ml (n = 298, p < 0.001). RBC TPMT activity is not affected by hemodialysis. The plasma of uremic patients reversibly inhibits RBC TPMT activity to a greater extent than normal plasma does and contains higher concentrations of endogenous methyl acceptors than normal plasma. Plasma TPMT inhibitors are not removed by hemodialysis. There are large individual variations in inhibition of RBC TPMT by plasma from patients with renal failure. Inhibition varied from 1% to 93% in 20 microliters of plasma from each of 20 randomly selected uremic patients. There was a positive correlation between the inhibition of TPMT and the content of endogenous methyl acceptors in uremic plasma (r = 0.914, n = 20, p < 0.001), but there was no significant correlation between degree of inhibition and urea nitrogen, serum creatinine, or hematocrit. The ability of plasma from individual uremic patients to inhibit TPMT also correlated with its ability to inhibit two other drug metabolizing methyltransferases in the RBC, catechol-O-methyltransferase and phenol-O-methyltransferase, RBC TMT activity is not altered in patients with uremia. The results of these and other studies of methyl conjugation in renal failure focus attention on the accumulation of methyl acceptor substrates in some of these patients and on the possible effects of these methyl acceptors on a variety of methylation reactions.
Asunto(s)
Eritrocitos/enzimología , Compuestos de Sulfhidrilo/sangre , Uremia/enzimología , Adolescente , Adulto , Anciano , Catecol O-Metiltransferasa/sangre , Inhibidores Enzimáticos/sangre , Femenino , Humanos , Riñón/enzimología , Masculino , Metilación , Metiltransferasas/sangre , Persona de Mediana Edad , Fenoles/sangre , Plasma/fisiología , Diálisis RenalRESUMEN
Thiopurine methyltransferase (TPMT) catalyzes thiopurine S-methylation, an important metabolic pathway for drugs such as 6-mercaptopurine. Erythrocyte (RBC) TPMT activity was measured in blood samples from 298 randomly selected subjects. Of the subjects, 88.6% were included in a subgroup with high enzyme activity (13.50 +/- 1.86 U, mean +/- SD), 11.1% were included in a subgroup with intermediate activity (7.20 +/- 1.08 U), and 0.3% had undetectable activity. This distribution conforms to Hardy-Weinberg predictions for the autosomal codominant inheritance of a pair of alleles for low and high TPMT activity, TPMT(L) and TPMT(H), with gene frequencies of .059 and .941, respectively. If RBC TPMT activity is inherited in an autosomal codominant fashion, then subjects homozygous for TPMT(H) would have high enzyme activity, subjects heterozygous for the two alleles would have intermediate activity, and subjects homozygous for TPMT(L) would have undetectable activity. The segregation of RBC TPMT activity among 215 first-degree relatives in 50 randomly selected families and among 35 members of two kindreds and one family selected because they included probands with undetectable RBC enzyme activity were also compatible with the autosomal codominant inheritance of RBC TPMT. For example, in eight matings between subjects with intermediate activity (presumed genotype TPMT(L)TPMT(H)) and subjects with high activity (presumed genotype TPMT(H)TPMT(H)), 47% (8/17) of the offspring had intermediate activity. This value is very similar to the 50% figure expected on the basis of autosomal codominant inheritance (chi(2) ([1]) = .059). Further experiments are required to determine whether this genetic polymorphism for an important drug metabolizing enzyme may represent one factor in individual variations in sensitivity to thiopurines.