Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “COMT”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,081 records · Page 60Linked to original sources
PubMed1983

Enzymatic O-methylation of the dopamine agonist dipropyl-5,6-dihydroxyaminotetralin: isolation and structure elucidation of the O-methylated metabolite.

The (+)-enantiomer of the potent dopamine agonist dipropyl-5,6-dihydroxyaminotetralin (DP-5,6-diOH-ATN) is metabolized in vitro by catechol-O-methyltransferase (COMT) to one O-methyl derivative. This compound was isolated from the incubation mixture by reversed-phase HPLC, after the incubation mixture had been purified over Sephadex G 10 columns and the excess parent catecholamine had been removed with alumina. One of the possible O-methyl metabolites, dipropyl-5-hydroxy-6-methoxyaminotetralin, was synthesized from dipropyl-5,6-dimethoxyaminotetralin by a regioselective mono-demethylation with iodotrimethylsilane. Comparison of chromatographic and spectral data of the products from incubation and synthesis showed that different isomers are formed; i,e. DP-5,6-diOH-ATN is exclusively meta-O-methylated by COMT in vitro to dipropyl-5-methoxy-6-hydroxyaminotetralin.

Animals↗
PubMed1994

Role of dopamine and other stimuli of mucosal bicarbonate secretion in duodenal protection.

Duodenal mucosal secretion of bicarbonate is one main mechanism in the protection of this epithelium against luminal acid. The duodenal secretagogue vasoactive intestinal polypeptide, at doses not affecting mucosal blood flow, protects against acid-induced morphological changes. Some sigma receptor ligands, which increase the duodenal alkaline secretion, prevent duodenal but not gastric mucosal ulceration. Dopamine D-1 receptor agonists and the peripherally acting catechol-O-methyl-transferase (COMT) inhibitor nitecapone stimulate the bicarbonate secretion in the rat and a similar increase in secretion has been observed in human volunteers. COMT inhibitors decrease tissue degradation of catecholamines, including dopamine. The D-2 agonist bromocriptine, in contrast, decreases the secretion. These results, indicating that the bicarbonate secretion is stimulated via peripheral dopamine D-1 receptors, are supported by the finding that dopamine D-1 (but not D-2) agonists increase the production of cyclic AMP in isolated duodenal enterocytes. The increase in mucosal alkaline secretion may contribute to the previously observed ulceroprotective actions of dopaminergic compounds.

Animals↗
PubMedDate not supplied

Some biological mechanisms of the inborn predisposition to alcoholism.

The children of alcoholism patients have a high biological risk of this illness, mental and emotional disorders, and behavioral disturbances. The offspring of white mongrel rats with chronic alcohol intoxication were investigated in order to study the neurochemical mechanisms of these phenomena. The content of DA in blood and blood plasma, the characteristics of GABA and the opiate receptors of the brain, the activity of DBH, COMT, MAO, the content of cAMP and cGMP in brain tissue, as well as the expression of the gene c-fos were studied. Changes in the brain content of DA and qualitative and quantitative changes in MAO (an increase and solubilization of MAO A and B activity in the liver) were identified in the offspring of alcoholic rats. A tendency was also observed in the brain toward a decrease in the activity of DBH and COMT and an increase in the activity of cAMP and cGMP. The baseline expression of the gene c-fos in the offspring of male alcoholic rats did not differ from the norm; however, a powerful increase in the expression of the gene c-fos did appear in response to the administration of 2 g/kg of ethanol, in the absence of this effect in the control. A view is presented on the significant role of changes in the functions of the DA system in the genesis of pathology in the offspring of parents with chronic alcohol intoxication, as well as on the possible influence of the prolonged consumption of alcohol on the function of the genome.

Alcoholism↗
PubMed1997

Tryptophan hydroxylase and catechol-O-methyltransferase gene polymorphisms: relationships to monoamine metabolite concentrations in CSF of healthy volunteers.

Concentrations of monoamine metabolites (MM) in lumbar cerebrospinal fluid (CSF) have been used extensively as indirect estimates of monoamine turnover in the brain. We investigated possible relationships between DNA polymorphisms in the tryptophan hydroxylase (TPH) and catechol-O-methyltransferase (COMT) genes and CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 66). Lower CSF 5-HIAA levels were found in men with the TPH U allele (p = 0.005), but not in women. A similar but less significant pattern was observed for CSF HVA. No relationship was found between the TPH polymorphism and CSF MHPG. COMT genotypes did not relate significantly to MM concentrations. The results suggest that TPH genotypes participate differentially in the regulation of serotonin turnover rate under presumed steady state in the central nervous system of men. Due to the uncertain functional relevance of the DNA polymorphism investigated and the many calculations performed, the results should be interpreted with caution until replicated.

Adult↗
PubMed1995

Effects of pargyline and pyrogallol on the methamphetamine-induced dopamine depletion.

The formation of 6-hydroxydopamine (6-OHDA) from dopamine (DA) was investigated in the striatum of male Sprague-Dawley rats following a single administration of methamphetamine hydrochloride (100 mg/kg, sc). Rats were sacrificed 30, 60, and 90 min, and 1 wk after injection, and striatal 6-OHDA, DA, and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured by HPLC with electrochemical detection. Methamphetamine decreased striatal DA and DOPAC levels (to 65 and 50% at 90 min, respectively) in the time-course study and also resulted in a long-lasting dopamine depletion (34%) 1 wk after its administration. However, endogenous 6-OHDA formation proved difficult to detect after administration of the methamphetamine alone. Pretreatment with the monoamine oxidase (MAO) inhibitor pargyline (100 mg/kg, ip) and the catechol-O-methyltransferase (COMT) inhibitor pyrogallol (25 mg/kg, ip) resulted in the HPLC detection of a 6-OHDA-like substance 30 min after methamphetamine administration when the oxidizing potential was set at 0.5 V, but not when it was set at 0.2 V. Moreover, pargyline (25 mg/kg, ip) alone or in combination with pyrogallol exacerbated the long-lasting dopamine depletion induced by methamphetamine (50 mg/kg, sc). These results indicate that simultaneous inhibition of MAO and COMT provides a cellular environment that encourages the autoxidation of dopamine to a 6-OHDA-like substance.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Entacapone increases and prolongs the central effects of l-DOPA in the 6-hydroxydopamine-lesioned rat.

Long-term palliative treatment of Parkinson's disease (PD) with the dopamine precursor l-3,4-dihydroxyphenylalanine ( l-DOPA, levodopa) is compromised by the occurrence of motor complications, most notably motor fluctuations and involuntary movements, l-DOPA-induced dyskinesias. This study was aimed at investigating the effect of adding the catechol- O-methyltransferase (COMT) inhibitor entacapone to chronic treatment with l-DOPA/benserazide. It was hoped that the administration of entacapone would prolong and smooth the central effect of l-DOPA exposure and that this would result in a reduced risk of l-DOPA-induced dyskinesia induction by lowering the l-DOPA dose. The rotational response and striatal extracellular dopamine release were assessed in rats that had undergone a unilateral 6-hydroxydopamine-induced lesion of the nigro-striatal system. Previous studies have shown that repeated treatment with l-DOPA is accompanied by a marked enhancement in behavioural responses and has pharmacological characteristics similar to l-DOPA-induced dyskinesia. In the present study, we demonstrated that rats receiving entacapone in addition to 6.50 mg/kg of l-DOPA displayed significant enhancement of the developing contralateral turning response compared with rats treated with the same dose of l-DOPA only. However, when reducing the l-DOPA dose to 4.25 mg/kg the behavioural response was comparable to that seen in rats treated with the higher dose of l-DOPA only. Voltammetry analysis suggests that the increased behavioural response in entacapone-treated rats is the result of a much larger dopamine release. In addition, we found that entacapone treatment prolonged and smoothed the striatal dopamine levels following chronic l-DOPA/benserazide treatment. From a clinical point of view, this finding suggests that administration of a COMT inhibitor should allow the frequency of l-DOPA administration to decrease and to smooth the brain delivery of the l-DOPA, which in the end should facilitate a reduction in the risk of dyskinesia induction.

Animals↗
PubMed2005

The effect of nicotine in combination with various dopaminergic drugs on nigrostriatal dopamine in rats.

It is well established that nicotine activates brain dopaminergic systems and in addition has neuroprotective actions. Thus, nicotinic acetylcholine receptor (nAChR) agonists might be beneficial in the treatment of Parkinson's disease, and it is important to study the interactions of nicotine with drugs affecting the nigrostriatal dopaminergic pathway. We used brain microdialysis to study the effects of nicotine on extracellular levels of dopamine (DA) and its metabolites in the rat dorsal striatum in combination with drugs inhibiting either DA uptake (nomifensine), catechol-O-methyltransferase (COMT; tolcapone), monoamine oxidase B (MAO-B; selegiline) or DA receptors (haloperidol). Nicotine (0.5 mg/kg, s.c.) modestly increased DA output, and this effect was antagonised by mecamylamine but not by hexamethonium. Nomifensine (3 mg/kg, i.p.) substantially further enhanced the nicotine-induced increase in DA output and nomifensine+nicotine also evoked a strong mecamylamine-sensitive ipsilateral rotational behaviour in 6-hydroxydopamine lesioned rats. Tolcapone (10 mg/kg, i.p.) did not alter DA output, but markedly decreased homovanillic acid (HVA) and increased 3,4-dihydroxyphenylacetic acid (DOPAC). Selegiline pretreatment (5 x 1 mg/kg, i.p.) significantly increased extracellular DA and decreased DOPAC and HVA. Haloperidol (0.1 mg/kg, s.c.) slightly increased DA output and more clearly DOPAC and HVA. Tolcapone, selegiline or haloperidol did not enhance the nicotine-induced DA output. These results indicate that the activation of nigrostriatal nAChRs induces a significant DA release in the striatum, which is potentiated by DA uptake inhibition but not by COMT, MAO-B or presynaptic DA receptor inhibition. Our findings therefore agree with the notion that the termination of the effect of DA in the synapse mainly occurs via neuronal reuptake. Thus, selective nAChR agonists, possibly in combination with a DA uptake inhibitor, might improve dopaminergic transmission in Parkinson's disease.

Animals↗
PubMed1999

The influence of animal age on beta-adrenoceptor density and function in tracheal airway smooth muscle.

We examined the influence of animal age on the functional response of guinea-pig (0-156 weeks) and rat (4-136 weeks) isolated tracheal tissue to beta-adrenoceptor agonists. In addition, the binding density and affinity of [125I]iodocyanopindolol ([125I]CYP) binding to tracheal tissue was examined with respect to animal age. Significant age-related changes in isoprenaline potency were observed in tracheal ring preparations taken from animals during the early maturation phase of animal growth in the guinea-pig and rat. In addition, in rat isolated tracheal tissue, age-related decreases in fenoterol potency were observed during senescence, but not maturation. The changes in the functional responsiveness of tracheal tissue were not reflected by changes in the binding density or affinity for [125I]cyanopindolol ([125I]CYP) of beta-adrenoceptors, or in changes in specific autoradiographic grain density over smooth muscle tissue. In both guinea-pig and rat, no significant age-related changes in the influence of catechol-O-methyl transferase (COMT) or of extraneuronal uptake inhibition were detected. This study has demonstrated significant age-related changes in the responsiveness of guinea-pig and rat isolated tracheal tissue to beta-adrenoceptor agonists that were not related to changes in the density or affinity of the beta-adrenoceptor population or in the activity of COMT or extraneuronal uptake. The possibility of age-related changes in receptor-signal transduction coupling should be explored.

Adrenergic beta-Agonists↗
PubMed2006

Tolcapone decreases plasma levels of S-adenosyl-L-homocysteine and homocysteine in treated Parkinson's disease patients.

BACKGROUND: Elevated plasma total homocysteine (tHcy) appeared in levodopa/dopadecarcoxylase inhibitor (DDI) treated patients with Parkinson's disease (PD). One therapeutic approach for tHcy reduction is vitamine supplementation, since folic acid and cobalamine catalyse and enhance metabolism of tHcy to methionine. A further therapeutic alternative is inhibition of catechol-O-methyltransfrase (COMT) on a regular basis, when levodopa/DDI treatment is performed. METHODS: We measured the concentrations of S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), tHcy, levodopa and 3-O-methyldopa in plasma of 13 levodopa treated PD patients before first drug intake at 0600 hours. Blood samples were taken before and after 2 days of additional application of the centrally acting catechol-O-methyltransferase inhibitor tolcapone 100 mg t.i.d. RESULTS: Plasma levels of SAH [day 1: 48.32+/-22.52, 23.92-98.25 (mean+/-SD, range; micromol/l); day 3: 37.72+/-15.84, 23.4-61.89; p = 0.01] and tHcy (day 1: 13.88+/-5.62, 7.63-24.81; day 3: 11.38+/-4.44, 5.98-20.45; p = 0.04) significantly reduced. Plasma levels of levodopa did not significantly (p = 0.17) increase, whereas 3-OMD concentrations significantly (p = 0.0002) reduced after additional tolcapone intake. There was no significant change of SAM plasma levels (p = 0.22). CONCLUSION: Our prospective trial shows, that COMT inhibition with tolcapone lowers tHcy synthesis. Tolcapone may also possess beside its proven, occasional, hepatotoxic potency also beneficial effects via decrease of SAH and tHcy. This may hypothetically reduce homocysteine mediated progress of neuronal degeneration and the risk for onset of dementia, vascular disease and polyneuropathy in levodopa treated PD patients in the long term.

Aged↗
PubMed2000

Wood formation in poplar: identification, characterization, and seasonal variation of xylem proteins.

Proteins that are preferentially produced in developing xylem may play a substantial role in xylogenesis. To reveal the identity of these proteins, comparative two-dimensional polyacrylamide gel electrophoresis was performed on young differentiating xylem, mature xylem, and bark of poplar (Populus trichocarpa Hook. cv. 'Trichobel') harvested at different times of the year. The most-abundant xylem proteins were identified by microsequence analysis. For 17 of these proteins a putative function could be assigned based on similarity with previously characterized proteins, and for 15 out of these corresponding expressed sequence tags (ESTs) were found in the poplar EST database. The identified xylem-preferential proteins, defined by comparing the protein patterns from xylem and bark, were all involved in the phenylpropanoid pathway: two caffeoyl-coenzyme A O-methyltransferases (CCoAOMT), one phenylcoumaran benzylic ether reductase (PCBER), one bispecific caffeic acid/5-hydroxyferulic acid O-methyltransferase (COMT), five S-adenosyl-L-methionine synthetases, and one homologue of glycine hydroxymethyltransferase (GHMT). Remarkably, the biological function of the two most-abundant xylem-preferential proteins (PCBER and a GHMT homologue) remains unclear. In addition, several housekeeping enzymes were identified: two enolases, two glutamine synthetases, one 70-kDa heat-shock cognate, one calreticulin, and one alpha-tubulin. In comparison to the xylem-preferential proteins, the housekeeping proteins were expressed at significant levels in the bark as well. Also, several additional protein spots were detected for CCoAOMT, PCBER, and COMT by immunoblot. Our data show that for the study of xylogenesis, two-dimensional protein gel comparisons combined with systematic protein sequencing may yield information complementary to that from EST sequencing strategies.

Amino Acid Sequence↗
PubMed2004

[In search of susceptibility genes for schizophrenia].

After the recent discovery and replication of several schizophrenia candidate regions on multiple chromosomes, susceptibility genes for schizophrenia could be identified for the first time. Each of these discoveries resulted from association studies within chromosomal regions first identified by linkage analyses. Within the last two years, the susceptibility genes Neuregulin1, Dysbindin, D-amino-acid-oxidase (DAAO) and G72 were discovered, which, in the variant forms, reduce glutamatergic activity in brain. Therefore, they are related to the so-called "Glutamate-hypothesis", which postulates a hypofunction of the glutamatergic system. Adults with VCFS (velo-cardio-facial-syndrome), where a deletion on chromosome 22q11 can be found, show a very high incidence of schizophrenia. In addition, 2% of patients with schizophrenia exhibit this 22q11-deletion. Within the VCFS-deleted region on chromosome 22q11, the genes coding for proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT) were also found to be significantly associated with schizophrenia. Proline is a pre-stage of glutamate, and in addition, it seems to be a neuromodulator of glutamatergic transmission in the brain. COMT is one of the two enzymes degrading catecholamines such as dopamine. Therefore, it plays a large role in the cortical dopamine metabolism. Furthermore, an association of schizophrenia with the gene RGS4 (regulator-of-G-protein-signaling-4), a modulator of the function of multiple G-protein-linked neurotransmitter receptors, was identified. Gene-expression-analyses of postmortem cerebral cortex (prefrontal) indicate that the transcription of RGS4 is diminished within schizophrenics. In accordance with the fact that schizophrenia is a disease with a multifactorial etiology, it should be emphasized that the described biological risk factors can increase susceptibility, but that none of them can cause the disease alone.

Abnormalities, Multiple↗
PubMed2004

Elevated S-adenosylhomocysteine in Alzheimer brain: influence on methyltransferases and cognitive function.

Hyperhomocysteinemia is common in Alzheimer's disease and is negatively correlated with cognitive function. Hyperhomocysteinemia can increase S-adenosylhomocysteine (SAH), a potent methyltransferase inhibitor. This study investigates the role of brain SAH in the cognitive and neurological disruption in Alzheimer's disease. SAH was significantly (26%) higher in prefrontal cortex of Alzheimer patients than normals. Brain homogenates from Alzheimer patients inhibited an exogenous methyltransferase 15% more than normal homogenates (P <.001). Brain SAH levels correlated (r=.508) with methyltransferase inhibition by brain homogenates. Methyltransferase inhibition by Alzheimer brain homogenates correlated inversely with cognitive function as determined by MMSE (r=-0.36). Phenylethanolamine N-methyltransferase (PNMT) and catechol O-methyltransferase (COMT) activities were more than 30% lower (P<0.001) in Alzheimer than normal brains. Brain PNMT activity correlated significantly with cognitive function (r=0.243), age of Alzheimer's onset (r=0.272), and choline acetyltransferase activity (r=0.333), but negatively with neurofibrillary tangles (r=-0.332). COMT activity also correlated significantly with cognitive function (r=0.324), age of disease onset (r=0.209), choline acetyltransferase activity (r=0.326), levels of synaptophysin (r=0.506), and negatively with tangles (r=-0.216 P=0.039). Elevated SAH in Alzheimer brain inhibits methyltransferases and is related to markers of disease progression and cognitive impairment.

Adult↗
PubMed2005

Inferring candidate genes for attention deficit hyperactivity disorder (ADHD) assessed by the World Health Organization Adult ADHD Self-Report Scale (ASRS).

The present study tests the psychometric properties and validity of the German version of the World Health Organization Adult Attention Deficit Hyperactivity Disorder (ADHD) Self-Report Scale (ASRS), which is a short screening instrument for use in the general population. Furthermore, two candidate genes for ADHD, the COMT VAL158MET and the 5-HT2a T102C polymorphisms, were tested for associations with the ASRS subscales inattention and hyperactivity/impulsivity in N = 203 healthy subjects. The ordinal CFA yielded a two-factorial model corroborating the structure of the official English WHO version. Genetic analysis revealed an association between the VAL allele of COMT and the inattention scale (F(1, 201) = 7.20, p = 0.008), the hyperactivity/impulsivity scale (F(1, 201) = 4.30, p = 0.039), and the total ASRS scale (F(2, 201) = 7.64, p = 0.006) with highest scores in carriers of the MET/MET genotype. The C-allele of 5-HT2a was significantly associated with the hyperactivity/impulsivity scale (F(1, 201) = 5.52, p = 0.020) and the total ASRS scale (F(1, 201) = 4.21, p = 0.042) with highest scores in carriers of the TT genotype. The data provide evidence for the structural as well as for the external validity of the ASRS.

Attention Deficit Disorder with Hyperactivity↗
PubMed2002

Different modes of action of catecholamine-O-methyltransferase inhibitors entacapone and tolcapone on adenylyl cyclase activity in vitro.

Catechol-O-methyltransferase (COMT) inhibitors such as entacapone and tolcapone are used as adjuncts to L-DOPA ( l-3,4-dihydroxyphenylalanine, levodopa) in the treatment of Parkinson's disease. Tolcapone has been reported to associate with diarrhoea, a common reason for study withdrawal. The mechanism of this adverse effect is not yet understood. Cholera toxin causes diarrhoea by permanent activation of G(s) proteins, resulting in increased adenylyl cyclase (AC) activity. The aim of this study was to examine the effects of the COMT inhibitors entacapone and tolcapone on AC activity in membranes isolated from rat striatum, a brain structure enriched with dopaminergic G-protein-coupled receptors and AC activity. This study demonstrates differential effects of tolcapone and entacapone on Gpp(NH)p/dopamine-stimulated AC activity. Entacapone enhanced the stimulatory effect of Gpp(NH)p/dopamine, whereas tolcapone attentuated this effect, suggesting that diarrhoea associated with tolcapone treatment is not caused by permanent activation of G(s) proteins.

Adenylyl Cyclase Inhibitors↗
PubMed2001

Identification of 197 genetic variations in six human methyltranferase genes in the Japanese population.

Methylation is an important event in the biotransformation pathway for many drugs and xenobiotic compounds. We screened DNA from 48 Japanese individuals for single-nucleotide polymorphisms (SNPs) in six methyltransferase (MT) genes (catechol-O-MT, COMT; guanidinoacetate N-MT, GAMT; histamine N-MT, HNMT; nicotinamide N-MT, NNMT; phosphatidylethanolamine N-MT, PEMT; and phenylethanolamine N-MT, PNMT) by direct sequencing of their entire genomic regions except for repetitive elements. This approach identified 190 SNPs and seven insertion/deletion polymorphisms among the six genes. Of the 190 SNPs, 33 were identified in the COMT gene, 6 in GAMT, 41 in HNMT, 8 in NNMT, 98 in PEMT, and 4 in PNMT. Nine were located in 5' flanking regions, 156 in introns, 10 in exons, and 15 in 3' flanking regions. These variants may contribute to a more precise understanding of possible correlations between genotypes and disease-susceptibility phenotypes or risk for side effects from drugs.

3' Untranslated Regions↗
PubMed2006

Variants in estrogen metabolism and biosynthesis genes and urinary estrogen metabolites in women with a family history of breast cancer.

We examined associations between polymorphisms in genes related to estrogen metabolism (CYP1B1 codon 432G --> C rs#1056836, CYP1B1 codon 453A --> G rs#1800440, COMT codon 158G --> A rs#4680) and biosynthesis (CYP17 T --> C promoter rs#743572, CYP19 exon 4 TTTA repeat) and urinary estrogen metabolites (2-hydroxyestrogens (2-OHE), 16alpha-hydroxyestrone (16alpha-OHE1), and their ratio) in a pilot study of 64 pre- and post-menopausal women with a family history of breast cancer. Women were participants in the Metropolitan New York Registry of Breast Cancer Families, one of six international sites of the National Cancer Institute's Breast Cancer Family Registry. We used linear regression to examine the effects of genetic variants on log-transformed urinary estrogen metabolites. After adjusting for menopausal status, BMI, and age, carriers of the CYP1B1 codon 453G variant allele had 31.0% lower levels of 2-OHE (P-value = 0.05) and 40.2% lower levels of 16alpha-OHE1 (P = 0.01). Results were similar after restricting the analyses to pre-menopausal women (n = 41). Consistent with other studies, among pre-menopausal women, carriers of the COMT codon 158A variant allele had increased 2-OHE levels (P = 0.03) and an increased 2-OHE/16alpha-OHE1 ratio (P = 0.04); carriers of the CYP17 C promoter variant allele had increased 2-OHE levels (P = 0.08). To our knowledge this is the first report showing associations between the CYP1B1 codon 453G variant allele and urinary 2-OHE and 16alpha-OHE1 metabolites. Further larger studies should be conducted to confirm these results. Future identification of individuals with genetic polymorphisms that affect estrogen metabolism and biosynthesis may help characterize women at higher breast cancer risk and could guide breast cancer prevention strategies for those individuals.

Adult↗
PubMed2006

Pharmacogenomics: catechol O-methyltransferase to thiopurine S-methyltransferase.

1. Pharmacogenomics is the study of the role of inheritance in variation in the drug response phenotype-a phenotype that can vary from adverse drug reactions at one end of the spectrum to lack of therapeutic efficacy at the other. 2. The thiopurine S-methyltransferase (TPMT) genetic polymorphism represents one of the best characterized and most clinically relevant examples of pharmacogenomics. This polymorphism has also served as a valuable "model system" for studies of the ways in which variation in DNA sequence might influence function. 3. The discovery and characterization of the TPMT polymorphism grew directly out of pharmacogenomic studies of catechol O-methyltransferase (COMT), an enzyme discovered by Julius (Julie) Axelrod and his coworkers. 4. This review will outline the process by which common, functionally significant genetic polymorphisms for both COMT and TPMT were discovered and will use these two methyltransferase enzymes to illustrate general principles of pharmacogenomic research-both basic mechanistic and clinical translational research-principles that have been applied to a series of genes encoding methyltransferase enzymes.

Animals↗
PubMed1983

Catechol-O-methyltransferase activity in erythrocytes of pregnant women with sickle cell disease before, during, and after transfusion and partial exchange transfusion.

In the present investigation we found that the catechol-O-methyltransferase (COMT) activity in erythrocytes of pregnant women with sickle cell disease was strikingly elevated compared with that in erythrocytes of men and pregnant and nonpregnant women. Moreover, the enzyme activity in erythrocytes remained high during and after transfusion or partial exchange transfusion even though the enzyme activity in donor cells was low. This finding is suggestive of the possibility that a factor(s) in plasma of persons with sickle cell disease activates erythrocyte COMT activity.

Anemia, Sickle Cell↗