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Human thiopurine methyltransferase pharmacogenetics: effect of phenotype on sensitivity of cultured lymphocytes to 6-mercaptopurine

Conference · · Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States)
OSTI ID:6859466
;
Thiopurine methyltransferase (EC 2.1.1.67, TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP). TPMT activity in human lymphocytes and other tissues is controlled by a common genetic polymorphism. These experiments were designed to study the relationship between TPMT phenotype and the effect of 6-MP on /sup 3/H-thymidine (/sup 3/H-TdR) incorporation into phytohemaglutinin (PHA) stimulated human peripheral blood lymphocytes. Lymphocytes were obtained from the blood of nine subjects, three subjects with each TPMT phenotype. 6-MP dose response curves were performed at optimal (10 ..mu..g/ml) and suboptimal (1 ..mu..g/ml) concentrations of PHA. ED50 values for 6-MP with lymphocytes from subjects who genetically lacked TPMT activity were higher than ED50 values for lymphocytes from subjects with genetically intermediate or high TPMT activity. However, ED50 values decreased as level of stimulation increased. Therefore, the effects of 6-MP were studied at a series of PHA concentrations that ranged from 0.1 ..mu..g/ml to 10 ..mu..g/ml. Lymphocytes from subjects who lacked TPMT activity had significantly higher K/sub ii/ values (1.37 +/- 0.340 ..mu..M; mean +/- SEM) for inhibition of /sup 3/H-TdR incorporation by 6-MP than did lymphocytes from subjects with intermediate or high TPMT activity (0.529 +/- 0.068 ..mu..M and 0.327 +/- 0.064 ..mu..M, respectively, P < .05 for both comparisons).
Research Organization:
Mayo Foundation, Rochester, MN
OSTI ID:
6859466
Report Number(s):
CONF-8604222-
Conference Information:
Journal Name: Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States) Journal Volume: 45:4
Country of Publication:
United States
Language:
English

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Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AGGLUTININS
ANIMAL CELLS
ANIMALS
ANTIBODIES
AZINES
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
CARBOHYDRATES
CELL CULTURES
CONNECTIVE TISSUE CELLS
DOSE-RESPONSE RELATIONSHIPS
ENZYME ACTIVITY
ENZYMES
HEMAGGLUTININS
HETEROCYCLIC COMPOUNDS
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
LEUKOCYTES
LYMPHOCYTES
MAMMALS
MAN
MATERIALS
MITOGENS
MUCOPROTEINS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PHENOTYPE
PHYTOHEMAGGLUTININ
POLYSACCHARIDES
PRIMATES
PROTEINS
PYRIMIDINES
REACTION KINETICS
RIBOSIDES
SACCHARIDES
SENSITIVITY
SOMATIC CELLS
THYMIDINE
TRACER TECHNIQUES
TRANSFERASES
TRITIUM COMPOUNDS
VERTEBRATES