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R Weinshilboum

Publications and source records attributed to R Weinshilboum.

At least 19 recordsLinked to original sources
PubMed1990

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.

Adolescent↗
PubMed1988

Phenol sulfotransferase inheritance.

1. Phenol sulfotransferase (PST) catalyzes the sulfate conjugation of many phenolic and catechol neurotransmitters. Human tissues contain both thermostable (TS) and thermolabile (TL) forms of PST that differ in their substrate specificities, inhibitor sensitivities, physical properties, and regulation. 2. Individual variations in the levels of activity of both TS and TL PST in the human platelet are strongly influenced by inheritance. 3. Individual differences in the level of platelet TS PST activity are correlated with individual variations in the activity of this form of the enzyme in human cerebral cortex, liver, and intestinal mucosa. 4. There are also individual familial differences in the thermal stability of TS PST in the platelet. These differences are correlated with individual variations in the thermal stability of TS PST in cerebral cortex, liver, and intestinal mucosa. 5. Individual variations in the thermal stability of TS PST in hepatic tissue are associated with the presence of one or both of a pair of TS PST isozymes that can be separated by ion-exchange chromatography and that differ in their thermal stabilities. 6. This series of observations suggests that a structural gene polymorphism may be one mechanism by which inheritance controls TS PST in humans. The isozymes of TS PST in liver may represent the products of alternative alleles for this polymorphism, alleles that might control the structure of TS PST in many human tissues.

Arylsulfotransferase↗
PubMed1988

Pharmacogenetics of methylation: relationship to drug metabolism.

Pharmacogenetics is the study of inherited variation in drug response. Genetic differences in drug metabolism are the most common causes for inherited variations in drug response or adverse reactions to medications. Methyl conjugation is an important pathway in the biotransformation of many drugs. Experiments performed during the past decade showed that individual variations in the activities of enzymes that catalyze S-methylation, O-methylation and N-methylation are under genetic control in human tissue. These inherited variations are responsible for individual differences in metabolism, effect, and toxicity of drugs that undergo methyl conjugation. The approach used to study the pharmacogenetics of methylation may also be applicable to the study of inherited variations in other pathways of drug metabolism.

Adult↗
PubMed1987

Human and rat liver phenol sulfotransferase: structure-activity relationships for phenolic substrates.

Phenol sulfotransferase (PST) catalyzes the sulfate conjugation of many phenolic drugs. Human liver contains thermostable (TS) and thermolabile forms of PST. Ion exchange chromatography shows that two isozymes of TS PST (peaks I and II) are present in human liver preparations. Rat liver contains four forms of PST that can be separated by ion exchange chromatography. Quantitative structure-activity relationship (QSAR) analysis was used to study phenolic substrates for both human and rat liver PST. Thirty-six substituted phenols were tested as substrates for partially purified human liver TS PST peak I. QSAR analysis resulted in derivation of the following equation: log 1/Km = 0.92 (+/- 0.18)log P - 1.48 (+/- 0.38)MR'4 - 0.64 (+/- 0.41)MR3 + 1.04 (+/- 0.63)MR2 + 0.67(+/- 0.44) sigma- + 4.03 (+/- 0.42). In this equation Km is the Michaelis constant, P is the octanol-water partition coefficient, MR is the molar refractivity of substituents at the 2-, 3-, and 4-positions, and sigma- is the Hammett constant. Values of log 1/Km calculated with this equation were highly correlated with log 1/Km values (r = 0.950) that were observed experimentally. Nine phenols were also tested as substrates for partially purified human liver TS PST peak II. Log 1/Km values for these compounds were significantly correlated for the two isozymes of TS PST (r = 0.992, p less than 0.001). QSAR analysis was also used to derive equations that described the behavior of phenolic substrates for rat liver PST forms I and II. These equations differed substantially from the equation derived for compounds tested with human liver TS PST peak I. Therefore, the characteristics of the active sites of human liver TS PST peak I and rat liver PST forms I and II appear to differ. Application of these equations may make it possible to predict Km values of phenolic substrates for human liver TS PST and for rat liver PST forms I and II.

Animals↗
PubMed1986

Analysis of the distribution of erythrocyte sodium lithium countertransport in a sample representative of the general population.

Numerous studies of sodium-lithium countertransport (Na-Li CNT) have reported higher rates in essential hypertensives versus normotensive controls. We studied the distribution and the mode of inheritance of Na-Li CNT using a sample of 238 unrelated individuals and a sample of 245 individuals in 50 pedigrees all sampled from the population at large. The distribution of Na-Li CNT is continuous and bimodal. Our results indicate that there is a large genetic contribution to the distribution of Na-Li CNT. The hypothesis that the effect that causes bimodality is transmitted from generation to generation is supported by the fit to these data of a restricted transmission model with tau 2 = 0.749. We hypothesize that this deviation of tau 2 from its Mendelian expectation may be attributable to heterogeneity in the etiology of the bimodality in the Na-Li CNT distribution in the population at large.

Adolescent↗
PubMed1983

Thermolabile and thermostable human platelet phenol sulfotransferase. Substrate specificity and physical separation.

Human platelets contain at least two forms of phenol sulfotransferase (PST), a thermolabile (TL) form for which dopamine is a substrate and a thermostable (TS) form for which micromolar concentrations of phenol can serve as substrate. At higher concentrations phenol is also a substrate for the TL form. Studies of the regulation and the possible clinical value of measurements of platelet PST have been hampered because there is no specific substrate for the TS form of the enzyme. The purposes of these experiments were to determine whether there might be a better substrate than phenol for use in measurement of the activity of the TS form of platelet PST, and to attempt to physically separate the two forms of the platelet enzyme. The results of substrate kinetic, thermal stability, and inhibitor studies performed with platelet homogenates were all compatible with the conclusion that p-nitrophenol and 6-OH-melatonin were substrates for both the TS and TL forms of platelet PST. Norepinephrine, epinephrine and 5-OH-tryptamine were substrates for only the TL form. The apparent Km constants of the two forms of PST for p-nitrophenol differed by 7,100-fold when measured in platelet homogenates. This difference was 200 times greater than that which has been reported for phenol. Therefore, p-nitrophenol is the preferred substrate for measurement of the TS PST activity if interference by the TL activity is to be avoided. This information made it possible to use p-nitrophenol as a substrate in experiments designed to separate the two forms of platelet PST.(ABSTRACT TRUNCATED AT 250 WORDS)

Arylsulfotransferase↗
PubMed1977

Inheritance of low immunoreactive human plasma dopamine-beta-hydroxylase. Radioimmunoassay studies.

Inheritance plays an important role in the determination of human plasma dopamine-beta-hydroxylase (DBH) enzymatic activity. It has been demonstrated that an allele (d) for very low enzymatic plasma DBH is inherited as an autosomal recessive trait. A radioimmunoassay for human DBH was developed to test the hypothesis that the presence of this allele results in a decrease in plasma DBH protein levels. The mean immunoreactive DBH (IDBH) in blood from a randomly selected population of adolescents was 824+/-38 ng/ml (mean+/-SEM, n = 134). The correlation coefficient of enzymatic DBH with IDBH for this group of 134 adolescents was 0.84 (P < 0.001). Of these subjects, 3.7% had values of < 100 ng/ml and appeared to compose a separate subgroup analogous to the 3-4% of the population that is homozygous for the allele for low enzymatic activity. There was a significant sibling-sibling correlation of IDBH values in the 14 sibling pairs included among the 134 subjects studied (r = 0.60, P < 0.025). IDBH was also measured in blood from 56 subjects homozygous (dd) for the allele for low enzymatic DBH (enzymatic activity < 50 U/ml) and in blood of 80 first-degree relatives of homozygous probands. All but two dd subjects had IDBH levels of <100 ng/ml. Results of family studies were compatible with the autosomal recessive inheritance of an allele for IDBH levels of less than 100 ng/ml which segregates with the allele for very low enzymatic activity. Average IDBH in blood of 37 obligate heterozygotes as determined by family studies (Dd) was 599+/-53 ng/ml (mean +/- SEM), significantly lower than the IDBH values found in a randomly selected population (P < 0.005). These results are compatible with the conclusion that the presence of the allele for low plasma enzymatic DBH results in a decrease in the quantity of DBH protein in human plasma.

Adolescent↗
PubMed1977

Dissociation of changes in enzymatic and immunoreactive rat serum dopamine bets-hydroxylase during growth and development.

Dopamine beta-hydroxylase (DBH) activity was measured in the serum, heart and salivary glands of Sprague-Dawley rats from 1 day after birth to 90 days of age. Serum DBH activity in blood from newborn animals was 90 units, approximately 4.5 times higher than in blood from 60- to 90-day-old rats. The serum enzyme activity increased to 130 units at 15 days of age and then decreased rapidly to adult levels (20 units). This decrease was not due to changes in levels of circulating inhibitors or activators of the enzyme. Four different inbred strains of rats also demonstrated a striking decrease in serum DBH activity between 15 and 60 days of age. Cardiac DBH in Sprague-Dawley rats increased approximately 5-fold from birth to 15 days of age, but failed to decrease thereafter. Salivary gland DBH activity also increased with maturation and failed to decrease. Plasma concentrations of epinephrine and norepinephrine were no different in blood samples obtained from Sprague-Dawley rats 15 and 60 days of age. This finding makes it less likely that the decrease in serum DBH activity with maturation represents a decrease in the functional activity of sympathetic nerve terminals. Antibodies against DBH were used to measure immunoreactive DBH protein in serum from rats 15 and 60 days of age. These studies demonstrated a significantly higher enzymatic activity per unit of immunoreactive protein in blood from young rats than in blood from animals 60 days of age. The ratios of enzymatic activity to immunoreactive protein as measured by the quantity of antibody necessary to precipitate 50% of the endogenous serum DBH activity (AD50) were 21.18 +/- 1.04 and 3.83 +/- 0.40 (mean +/- S.E.M.) for blood from animals 15 and 60 days of age, respectively. Among the possible explanations for this observation are included a greater quantity of enzymatically inactive but immunoreactive DBH in blood of adult animals as compared with the blood of young rats, or the existence of a different form of serum DBH in blood of young animals.

Aging↗
PubMed1976

Human serum dopamine beta-hydroxylase: correlation of enzymatic activity with immunoreactive protein in genetically defined samples.

An antibody against human adrenal dopamine beta-hydroxylase (DBH) was used to quantitate immunoreactive DBH protein in human serum by an immunoprecipitation technique. A significant correlation was found between DBH enzyme activity and immunoreactive DBH protein in randomly selected serum samples (r = 0.94; N = 38; p less than .001). Studies of sera from obligate heterozygotes and individuals homozygous for the allele responsible for very low serum DBH enzymatic activity were compatible with a genetically mediated decrease in the quantity of circulating DBH protein in these subjects.

Adrenal Glands↗
PubMed1972

Catecholamines.

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Adrenal Medulla↗