Inhibition of human erythrocyte phenol-O-methyltransferase in uremia

P. Pazmino, F. Rogoff, Richard M Weinshilboum

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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 from 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 uremic patients was tested. There is a direct correlation between the ability of 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, serum creatinine, or hematocrit. Kinetic studies with pooled uremic 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-methionine. The approach used in these experiments may serve as one model for future studies of the effect of renal failure on drug metabolism in individual patients.

Original languageEnglish (US)
Pages (from-to)464-472
Number of pages9
JournalClinical Pharmacology and Therapeutics
Volume26
Issue number4
StatePublished - 1979

Fingerprint

phenol O-methyltransferase
Uremia
Erythrocytes
Renal Insufficiency
Renal Dialysis
S-Adenosylmethionine
Membranes
Phenols
Blood Urea Nitrogen
Erythrocyte Membrane
Hematocrit
Methylation

ASJC Scopus subject areas

  • Pharmacology

Cite this

Inhibition of human erythrocyte phenol-O-methyltransferase in uremia. / Pazmino, P.; Rogoff, F.; Weinshilboum, Richard M.

In: Clinical Pharmacology and Therapeutics, Vol. 26, No. 4, 1979, p. 464-472.

Research output: Contribution to journalArticle

@article{faad71c4f37a421ab6c7257fd49e6977,
title = "Inhibition of human erythrocyte phenol-O-methyltransferase in uremia",
abstract = "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 from 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 uremic patients was tested. There is a direct correlation between the ability of 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, serum creatinine, or hematocrit. Kinetic studies with pooled uremic 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-methionine. The approach used in these experiments may serve as one model for future studies of the effect of renal failure on drug metabolism in individual patients.",
author = "P. Pazmino and F. Rogoff and Weinshilboum, {Richard M}",
year = "1979",
language = "English (US)",
volume = "26",
pages = "464--472",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - Inhibition of human erythrocyte phenol-O-methyltransferase in uremia

AU - Pazmino, P.

AU - Rogoff, F.

AU - Weinshilboum, Richard M

PY - 1979

Y1 - 1979

N2 - 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 from 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 uremic patients was tested. There is a direct correlation between the ability of 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, serum creatinine, or hematocrit. Kinetic studies with pooled uremic 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-methionine. The approach used in these experiments may serve as one model for future studies of the effect of renal failure on drug metabolism in individual patients.

AB - 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 from 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 uremic patients was tested. There is a direct correlation between the ability of 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, serum creatinine, or hematocrit. Kinetic studies with pooled uremic 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-methionine. The approach used in these experiments may serve as one model for future studies of the effect of renal failure on drug metabolism in individual patients.

UR - http://www.scopus.com/inward/record.url?scp=0018726069&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0018726069&partnerID=8YFLogxK

M3 - Article

C2 - 487694

AN - SCOPUS:0018726069

VL - 26

SP - 464

EP - 472

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 4

ER -