Human liver catechol-O-methyltransferase pharmacogenetics.
Catechol-O-methyltransferase activity and thermal stability in the human red blood cell are controlled by a common genetic polymorphism. Approximately 25% to 30% of a randomly selected population sample is homozygous for the traits of low catechol-O-methyltransferase activity and thermolabile enzyme in the red blood cell. We tested the hypothesis that the catechol-O-methyltransferase genetic polymorphism might also control those same characteristics of the enzyme in an important human drug-metabolizing organ, the liver. Catechol-O-methyltransferase enzyme activity and thermal stability were measured in 99 hepatic biopsy samples obtained during clinically indicated surgery. The frequency distribution of heated/control ratios, a measure of enzyme thermal stability, was bimodal, with 28% of samples included in a subgroup with thermolabile enzyme. There were no sex-related differences in hepatic catechol-O-methyltransferase thermal stability. However, catechol-O-methyltransferase enzyme activity in hepatic tissue from male subjects was significantly higher than that in samples from female subjects: 61.3 +/- 20.2 units/mg protein (mean +/- SD; n = 50) versus 46.6 +/- 22.2 units/mg protein (n = 49; p = 0.0002). There was a significant correlation of hepatic catechol-O-methyltransferase activity and thermal stability in samples from both female (rs = 0.698; p = 0.0001) and male subjects (rs = 0.429; p = 0.002). Finally, when both red blood cell catechol-O-methyltransferase activity and thermal stability were measured in blood samples from 34 of these patients, there was a significant correlation between catechol-O-methyltransferase heated/control ratios and levels of enzyme activity in hepatic tissue and in red blood cell lysates. These findings indicate that the genetic polymorphism that controls catechol-O-methyltransferase activity level and thermal stability in red blood cells also controls those same properties of the enzyme in the human liver.
Boudíková
B
B
Department of Pharmacology, Mayo Clinic, Rochester, MN 55905.
Szumlanski
C
C
Maidak
B
B
Weinshilboum
R
R
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D002648:Child; D004795:Enzyme Stability; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D006358:Hot Temperature; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic
D002394:Catechol O-Methyltransferase