Inhibition of human erythrocyte phenol-O-methyltransferase in uremia

Phenol-O-methyltransferase (PMT) catalyzes the methylation of a variety of phenols. PMT activity is present in human erythrocyte (RBC) Membranes. The enzyme activity is less in RBC membranes from uremic patients on maintenance hemodialysis, 98.1 ± 4.4 U/mg membrane protein (mean ± SEM, n = 51), than in blood from randomly selected subjects, 134.5 ± 2.9 (n = 212, p < 0.001). There is no change in RBC PMT activity after hemodialysis. Uremic plasma contains methyl acceptors not present in normal plasma and reversibly inhibits PMT in RBC membranes frosts nonuremic subjects. There is considerable individual variation in the inhibition of RBC PMT by plasma samples from patients with renal failure e.g., inhibition varied from 0% to 47% when 20 μl of plasma from each of 21 randomly selected urernic patients was tested. There is a direct correlation between the ability q/ individual samples of plasma from uremic patients to inhibit PMT activity and their content of endogenous methyl acceptors (r = 0.91, n = 21, p < 0.001) but there is no correlation between the level of inhibition and such clinical laboratory values as blood urea nitrogen, scrum creatinine, or hematocrit. Kinetic studies with pooled urernic plasma show that the inhibition of PMT is noncompetitive with respect to the phenolic substrate, but is competitive with respect to the methyl donor, S-adenosyl-L-nicthionine. The approach used in these experiments may serve is one model for future studies of the effect of renal failure on drug metabolism in individual patients.