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PubMed1994

O-methylation of L-dopa in melanin metabolism and the presence of catechol-O-methyltransferase in melanocytes.

O-Methylation of L-dopa was investigated as a possible regulatory mechanism in melanin metabolism. The methylation product of L-dopa, 3-O-methoxytyrosine was detected in extracts of cultured human melanocytes. The enzyme catechol-O-methyltransferase is responsible for this O-methylation and that of the dihydroxyindolic intermediates of melanogenesis. The enzyme is present in melanocytes in its soluble and membrane-bound isoforms. Immuno-electron microscopy suggests the presence of the membrane-bound enzyme in the endoplasmic reticulum. This localization may indicate a role of catechol-O-methyltransferase in protecting the melanocyte against reactive dihydroxyphenolic intermediates of melanogenesis leaking from the melanogenic compartments. On the other hand, the O-methylation of L-dopa may serve as a regulatory point in melanogenesis during early stage of tyrosinase processing in the endoplasmic reticulum.

1-Methyl-3-isobutylxanthine↗
PubMed1999

Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription.

Catechol-O-methyltransferase (COMT, EC 2.1.1.6) is a ubiquitous enzyme that is crucial to the metabolism of carcinogenic catechols and catecholamines. Regulation of human COMT gene expression may be important in the pathophysiology of various human disorders including estrogen-induced cancers, Parkinson's disease, depression, and hypertension. The gender difference in human COMT activity and variations in rat COMT activity during the estrous cycle led us to explore whether estrogen can regulate human COMT gene transcription. Our Northern analyses showed that physiological concentrations of 17-beta-estradiol (10(-9)-10(-7) M) could decrease human 1. 3-kilobase COMT mRNA levels in MCF-7 cells in a time- and dose-dependent manner through an estrogen receptor-dependent mechanism. Two DNA fragments immediately 5' to the published human COMT gene proximal and distal promoters were cloned. Sequence analyses revealed several half-palindromic estrogen response elements and CCAAT/enhancer binding protein sites. By cotransfecting COMT promoter-chloramphenicol acetyltransferase reporter genes with human estrogen receptor cDNA and pSV-beta-galactosidase plasmids into COS-7 cells, we showed that 17-beta-estradiol could down-regulate chloramphenicol acetyltransferase activities, and COMT promoter activities dose-dependently. Functional deletion analyses of COMT promoters also showed that this estrogenic effect was mediated by a 280 base pair fragment with two putative half-palindromic estrogen response elements in the proximal promoter and a 323-base pair fragment with two putative CCAAT/enhancer binding protein sites in the distal promoter. Our findings provide the first evidence and molecular mechanism for estrogen to inhibit COMT gene transcription, which may shed new insight into the role of estrogen in the pathophysiology of different human disorders.

Animals↗
PubMed1970

Reduced catechol-O-methyltransferase activity in red blood cells of women with primary affective disorder.

Red blood cell catechol-O-methyltransferase, histamine-N-methyltransferase, and a methanol-forming enzyme were examined in a number of subjects with mental diseases. Catechol-O-methyltransferase activity was significantly reduced in female subjects with primary affective disorder (depression) as compared to normal women and men, men with primary affective disorder, and schizophrenic men and women. In depressed women, histamine-N-methyltransferase activity was elevated and the methanol-forming enzyme was unchanged.

Catechols↗
PubMed1988

Iron-regulated outer membrane proteins of Escherichia coli K-12 and mechanism of action of catechol-substituted cephalosporins.

Selected aminothiazolyl-oxime cephalosporin congeners substituted at C-3' with a catechol moiety were used to probe the basis of the enhanced antibacterial activity against Escherichia coli K-12 often associated with chemical modifications of this type. Evidence is presented for a tonB-dependent illicit transport of the compounds across the outer membrane of E. coli K-12, the process involving jointly and specifically the Fiu and Cir iron-regulated outer membrane proteins. Thus, both tonB and fiu cir mutants showed a comparably reduced susceptibility to the probe compounds, whereas mutants singularly lacking any one of the six iron-regulated outer membrane proteins (Fiu, FepA, FecA, FhuA, FhuE, and Cir) or lacking any combination of any two of these proteins (except Fiu plus Cir) did not show this resistance. Mutants devoid of all six iron-regulated outer membrane proteins were no more resistant to the probe compounds than fiu cir or tonB strains. In addition to the latter genes, the products of the exbB and possibly the exbC loci were necessary for maximal antibacterial potency. A dependence of antibacterial activity on the level of expression of the uptake system components was noted. Comparison of penicillin-binding protein target affinity with antibacterial activity suggested a possible periplasmic accumulation of active compounds by E. coli K-12. Free vicinal hydroxyl groups of the catechol residue were a primary chemical requirement for recognition by the uptake pathway and thus for high antibacterial activity.

Bacterial Outer Membrane Proteins↗
PubMed2005

Formation of catechols via removal of acid side chains from ibuprofen and related aromatic acids.

Although ibuprofen [2-(4-isobutylphenyl)-propionic acid] is one of the most widely consumed drugs in the world, little is known regarding its degradation by environmental bacteria. Sphingomonas sp. strain Ibu-2 was isolated from a wastewater treatment plant based on its ability to use ibuprofen as a sole carbon and energy source. A slight preference toward the R enantiomer was observed, though both ibuprofen enantiomers were metabolized. A yellow color, indicative of meta-cleavage, accumulated transiently in the culture supernatant when Ibu-2 was grown on ibuprofen. When and only when 3-flurocatechol was used to poison the meta-cleavage system, isobutylcatechol was identified in the culture supernatant via gas chromatography-mass spectrometry analysis. Ibuprofen-induced washed-cell suspensions also metabolized phenylacetic acid and 2-phenylpropionic acid to catechol, while 3- and 4-tolylacetic acids and 2-(4-tolyl)-propionic acid were metabolized to the corresponding methyl catechols before ring cleavage. These data suggest that, in contrast to the widely distributed coenzyme A ligase, homogentisate, or homoprotocatechuate pathway for metabolism of phenylacetic acid and similar compounds, Ibu-2 removes the acidic side chain of ibuprofen and related compounds prior to ring cleavage.

Catechols↗
PubMed1994

Characterization of the Vibrio anguillarum fur gene: role in regulation of expression of the FatA outer membrane protein and catechols.

The chromosomally encoded Vibrio anguillarum fur gene was characterized. The amino acid sequence of the Fur protein showed a very high degree of homology with those of V. cholerae and V. vulnificus. The degree of homology was lower, although still high, with the Escherichia coli and Yersinia pestis Fur amino acid sequences, while the lowest degree of homology was found with the Pseudomonas aeruginosa Fur protein. The C-terminal portion of Fur is the least conserved region among these Fur proteins. Within this portion, two regions spanning amino acids 105 to 121 and 132 to the end are the least conserved. A certain degree of variation is also present in the N termini spanning amino acids 28 to 46. Regulation of expression of the V. anguillarum fur gene by iron was not detected by immunoblot analysis. Mutations in the cloned fur gene were generated either by site-directed mutagenesis (the Lys-77 was changed to a Gly to generate the derivative FurG77) or by insertion of a DNA fragment harboring the aph gene in the same position. FurG77 was impaired in its ability to regulate a reporter gene with the Fur box in its promoter, while the insertion mutant was completely inactive. V. anguillarum fur mutants were obtained by isolating manganese-resistant derivatives. In one of these mutants, which encoded a Fur protein with an apparent lower molecular weight, the regulation of the production of catechols and synthesis of the outer membrane protein FatA were partially lost. In the case of another mutant, no protein was detected by anti-Fur serum. This derivative showed a total lack of regulation of biosynthesis of catechols and FatA protein by iron.

Amino Acid Sequence↗
PubMed1977

Solubilization and partial purification of particulate catechol-O-methyltransferase from rat liver.

Particulate catechol-O-methyltransferase (COMT) from rat liver has been solubilized by acetone treatment and partially purified. Results from the present study demonstrate that the solubilized, partially purified enzyme is similar to the cytosol COMT with respect to molecular weight, pH profile, sensitivity toward inhibitors, Mg2+ requirement, and substrate affinities. However, a comparison of the crude particulate COMT and the solubilized enzyme shows that there is a significant difference in their affinity for catechol substrates. This finding suggests that membrane protein and (or) lipid components may play an important role in catecholamine metabolism. The relationship of particulate COMT to [3H]norepinephrine binding was investigated. No correlation between the COMT and [3H]norepinephrine binding activities was observed in vitro.

Animals↗
PubMed1977

Red blood cell catechol O-methyltransferase activity in thyroid dysfunction.

Using a modification of the method of Mannl et al. (Mannl, H.F.K., Hempel, K., and Kubler, W. 1972. Catechol O-methyltransferase in human erythrocytes. Arch. Pharmacol. 272, 265-276), we have measured the activity of catechol O-methyltransferase (COMT) (EC 2.1.1.6) in red blood cells (RBC) of patients with hyperthyroidism and hypothyroidism to establish whether thyroid dysfunction is associated with alterations in catecholamine catabolism. The activity of COMT averaged 4.4+/-0.54 nmol/ml RBC per hour of incubation (mean+/-SEM) in euthyroid subjects compared to 4.76+/-0.64 nmol/ml RBC per hour of incubation in hyperthyroidism and 4.42+/-0.81 nmol/ml RBC per hour of incubation in hypothyroidism; these values are not significantly different. There were no significant differences observed in urinary excretion of vanillylmandelic acid, epinephrine, and norepinephrine among the three groups. These data are compatible with the possibility that thyroid status has little influence on the degradation of circulating catecholamines and suggest that hypothyroidism, with its attendant elevations in serum norepinephrine concentration, may be related to a compensatory noradrenergic response.

Catechol O-Methyltransferase↗
PubMed1999

Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase.

Methyl conjugation is an important pathway in the biotransformation of many exogenous and endogenous compounds. Pharmacogenetic studies of methyltransferase enzymes have resulted in the identification and characterization of functionally important common genetic polymorphisms for catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. In recent years, characterization of these genetic polymorphisms has been extended to include the cloning of cDNAs and genes, as well as a determination of the molecular basis for the effects of inheritance on these methyltransferase enzymes. The thiopurine methyltransferase genetic polymorphism is responsible for clinically significant individual variations in the toxicity and therapeutic efficacy of thiopurine drugs such as 6-mercaptopurine. Phenotyping for the thiopurine methyltransferase genetic polymorphism represents one of the first examples in which testing for a pharmacogenetic variant has entered standard clinical practice. The full functional implications of pharmacogenetic variation in the activities of catechol O-methyltransferase and histamine N-methyltransferase remain to be determined. Finally, experimental strategies used to study methylation pharmacogenetics illustrate the rapid evolution of biochemical, pharmacologic, molecular, and genomic approaches that have been used to determine the role of inheritance in variation in drug metabolism, effect, and toxicity.

Animals↗
PubMed1994

Roles of uptake1 and catechol-O-methyltransferase in removal of circulating catecholamines in the rabbit.

Anesthetized rabbits were simultaneously infused with [3H]norepinephrine (NE), [3H]epinephrine (Epi), [3H]dopamine (DA), and [3H]isoproterenol (Iso), and their plasma clearances and fractional extractions across the systemic (ERS), as well as pulmonary (ERP), circulation were determined before and after blockade of uptake1 by desipramine (2 mg/kg). Desipramine reduced the clearance of NE, Epi, and DA by 39, 13, and 14%, respectively, but did not affect Iso clearance. Similar results were obtained with respect to the effects of desipramine on ERS. By contrast, desipramine reduced ERP of NE and DA (which for both amines was markedly lower than ERS) by > 70%; its effect on the very low ERP of Epi was not determinable. Comparison of the desipramine-sensitive components of ERS and ERP indicated that for uptake1 NE was the preferred substrate in the systemic circulation and DA was preferred in the pulmonary circulation. In the absence and presence of desipramine, catechol-O-methyltransferase inhibition had no effect on the clearance of NE, Epi, and DA and decreased Iso clearance by 25%. Hence the contribution by uptake1 to the removal of circulating catecholamines depends on the type of amine and on whether the systemic or pulmonary circulation is considered. Moreover catechol-O-methyltransferase does not appear to contribute to the clearance of NE, Epi, and DA but plays a definite role in the removal of circulating Iso.

Animals↗
PubMed2006

Comprehensive assessment of genetic variation of catechol-O-methyltransferase and breast cancer risk.

Because catechol-O-methyltransferase (COMT) catalyzes the addition of methyl groups to stabilize catechol estrogens that may induce DNA damage, genetic variants could influence breast cancer risk. To comprehensively characterize genetic variation in this gene, we selected haplotype-tagging single nucleotide polymorphisms (htSNP) in COMT. A total of 11 htSNPs (including COMT Val(158)Met) were selected based on the resequencing and dense genotyping approach of the Breast and Prostate Cancer Cohort Consortium. htSNPs were genotyped in a population-based, case-control study in Poland (1,995 cases and 2,296 controls). Individual SNPs were not significantly associated with risk. Haplotypes were estimated using the expectation-maximization algorithm. Overall differences in the haplotype distribution between cases and controls were assessed using a global score test. The TGAG haplotype (frequent in 4.3% of controls), in a linkage disequilibrium (LD) block that included the 3' untranslated region (UTR) of COMT, was associated with breast cancer risk (odds ratio, 1.29; 95% confidence interval, 1.06-1.58) compared with the most common haplotype TGAA; however, the global test for haplotype associations was not significant (P = 0.09). Haplotypes in another LD block, which included COMT Val(158)Met, were not associated with breast cancer risk (global P = 0.76). Haplotype-breast cancer risk associations were not significantly modified by hormonally related risk factors, family history of breast cancer, or tumor characteristics. In summary, our data does not support a substantial overall association between COMT haplotypes and breast cancer. The suggestion of increased risk associated with a haplotype in the 3' UTR of COMT needs to be confirmed in independent study populations.

3' Untranslated Regions↗
PubMed2006

Catechol-O-methyltransferase gene polymorphisms in benign prostatic hyperplasia and sporadic prostate cancer.

Various carcinogenic metabolites, including catechol estrogens, play a role in malignant transformation. An enzyme that is capable of neutralizing the genotoxic effects of these compounds is catechol-O-methyltransferase (COMT). A variant form of this enzyme has been shown to reduce its activity by up to 4-fold; thus, we hypothesize that single nucleotide polymorphisms of the COMT gene can be a risk factor for benign prostatic hyperplasia (BPH) and prostate cancer. To test this hypothesis, the genetic distribution of three different COMT polymorphisms at codon 62 (C-->T), codon 72 (G-->T), and codon 158 (G-->A) were analyzed in 131 normal healthy subjects, 134 BPH, and 178 sporadic prostate cancer samples from a Japanese population. Results of these experiments show that the variant genotype at codon 62 (P = 0.060) and codon 158 (P = 0.047) are risk factors for prostate cancer but not BPH when compared with normal controls. Odds ratio (OR) and 95% confidence interval (95% CI) for cancer were 3.24 and 1.38 to 7.61, respectively, for codon 62 T/T genotype when compared with wild type. At codon 158, the A/A variant for cancer had an OR of 3.00 with a 95% CI of 1.38 to 6.54 compared with wild type. Codons 62 and 158 were in linkage disequilibrium (LD), and when compared with the C-G haplotype, other types (C-A, T-G, T-A) were observed to be associated with prostate cancer (P = 0.040) but not BPH. Codon 72 on the other hand, was not in LD with either codon 62 or 158. The homozygous variant on codon 72 was rare in this Japanese population, and the heterozygous G/T at this codon was not associated with either prostate cancer or BPH. When evaluating the risk of COMT polymorphisms with stage or grade of cancer, no associations were observed for any of the genotypes with the exception of a tendency (P = 0.096) for the variant A allele on codon 158 to be correlated with higher stages (> or = T3) of cancer. This is the first report that shows the polymorphisms of COMT to be associated with sporadic prostatic carcinogenesis. These results are important in understanding the role of COMT polymorphisms in the pathogenesis of prostate cancer.

Alleles↗
PubMed2007

Polymorphisms of catechol-O-methyltransferase in men with renal cell cancer.

The estrogen metabolite, 4-hydroxy-estrogen, has been shown to play a role in malignant transformation of male kidneys. To counteract the effects of this catechol-estrogen, the catechol-O-methyltransferase (COMT) enzyme is capable of neutralizing the genotoxic effects of this compound. A polymorphic variant of COMT has been shown to have a reduced enzyme activity, and thus, we hypothesize that single nucleotide polymorphisms of the COMT gene can be a risk factor for renal cell cancer (RCC). To determine this hypothesis, a study of a Japanese male population was used and the genetic distributions of COMT polymorphisms at codons 62 (C-->T), 72 (G-->T), and 158 (G-->A) were analyzed in 157 normal healthy subjects and 123 sporadic RCC (clear cell type) samples by using a sequence-specific PCR technique. These experiments show that the variant genotype (P = 0.025) and allele (P = 0.011) at codon 62 is a risk factor for RCC. The odds ratio and 95% confidence interval for cancer were 3.16 and 1.29 to 7.73, respectively, for the T/T genotype as compared with wild-type. No associations for renal cancer were found at either codons 72 or 158 in this Japanese male population. However, codons 62 and 158 were observed to be in linkage disequilibrium, and haplotype analysis shows the combined forms of T-A, T-G, and C-A to be associated with RCC as compared with C-G (P < 0.001). When evaluating the risk of COMT polymorphisms with grade of cancer, no associations were observed for any of the genotypes. This study is the first to report COMT polymorphism to be associated with RCC. These results are important in understanding the role of COMT polymorphisms in the pathogenesis of RCC.

Alleles↗
PubMed1982

Assay of human erythrocyte catechol-o-methyltransferase activity with naturally occurring catecholamines as substrates.

This report describes a simple and sensitive radiometric assay for catechol-o-methyltransferase activity in human erythrocytes and other tissues. Saturating concentrations of the endogenous catecholamines and S-adenosylmethionine are used under optimum assay conditions. Erythrocyte catechol-o-methyltransferase activity is also dependent on storage conditions, as activity was lost at -20 degrees C but not at -80 degrees C.

Catechol O-Methyltransferase↗
PubMed1981

Temporal and other effects of catechol estrogens on prolactin secretion in the rat.

Temporal alterations in plasma prolactin levels caused by the administration of 2-hydroxyestradiol and 2-hydroxyestrone (100 microgram/kg) into the right atrium of freely-moving conscious male rats were examined. The catechol estrogens were given in a single bolus via an indwelling cannula and plasma prolactin concentration was monitored by taking blood samples every 2 min. A pulsatile elevation of plasma prolactin occurred approximately 4 h after the injection of 2-hydroxyestradiol and a small increase was also observed when it was administered to rats bearing a Silastic capsule containing estradiol. 2-Hydroxyestrone had no effect in untreated male rats but produced a 5- to 6-fold elevation in plasma prolactin level 4 h after its administration to rats implanted with estradiol. It is proposed that 2-hydroxyestrone suppresses the action of estradiol on prolactin secretion from the pituitary and that the accumulated hormone is released when the concentration of this catechol estrogen falls below a critical level. A longer latent period was required to produce an elevation in plasma prolactin levels by 2-hydroxyestradiol than by estradiol.

Animals↗
PubMed1986

Effect of antihypertensive drugs on catechol-O-methyltransferase and monoamine oxidase activity in human term placental explants.

The effects of therapeutic concentrations of antihypertensive drugs on catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) activities in term placental explants were studied. The enzyme activities were measured in tissue fractions using radioenzymatic techniques. At 6 h the incubation COMT activity increased significantly following exposure to verapamil and hydralazine, while exposure to alpha methyldopa caused a significant suppression of the enzyme. At 24 h exposure to hydralazine significantly suppressed the COMT activity. By 6 h the MAO activity was significantly suppressed by verapamil. MgSO4 and propranolol had no effect on the activities of COMT and MAO at 6 and 24 h. These results suggest that COMT and MAO activities in the placenta can be modulated by antihypertensive drugs and, therefore, these drugs might affect local catechol metabolism.

Antihypertensive Agents↗
PubMed1994

Distribution of catechol-O-methyltransferase enzyme in rat tissues.

In the present study we show the distribution of catechol-O-methyltransferase (COMT) in various rat tissues with a highly specific antiserum prepared against recombinant rat COMT. Immunoprecipitation and immunocytochemical controls confirmed the COMT-specificity of the antibodies. The antiserum detected both the 24 KD soluble and the 28 KD membrane-bound forms of the enzyme. By immunohistochemical staining the COMT enzyme was found in most rat tissues. Staining was most intense in the liver and in the kidney, in agreement with previous studies and our immunoblotting results. In the gastrointestinal tract, epithelial cells of the stomach, duodenum, and ileum were immunoreactive for COMT. In pancreas, COMT immunoreactivity was found in insulin-producing beta-cells and somatostatin-producing D-cells but not in glucagon-producing alpha-cells of the islets of Langerhans. In pituitary, COMT immunoreactivity was found in cleft cells, in pituicytes of the posterior lobe, and in the anterior lobe, partly in the same cells containing luteinizing hormone (LH). In other endocrine organs, COMT immunoreactivity was found in epithelial cells of the thyroid gland and in zona glomerulosa of the adrenal cortex. In the brain, brightest immunofluorescence was seen in ependymal cells of the cerebral ventricles and choroid plexus. Weak to moderate immunofluorescence was found in the neuropil of several brain areas, including striatum and cortex. Scattered small neurons in spinal sensory ganglia were also COMT immunoreactive. Previous immunocytochemical studies, enzyme activity determinations, and distribution of the COMT mRNA are in general agreement with the results presented here. The wide distribution of COMT in different tissues suggests an important role for this protein in inactivation of catechol compounds.

Animals↗
PubMed1976

Catechol O-methyltransferase in red blood cells of schizophrenic, depressed, and normal human subjects.

Catechol O-methyltransferase of lysed human red blood cells was assayed under optimal conditions, using saturating concentrations of the substrates, S-adenosyl-L-methionine and 3-4-dihydroxybenzoic acid. The mean enzyme activity found in 24 normal subjects was 29-2 nmol/hr/ml RBC. The mean activity in blood of 33 female unipolar depressives was not significantly different from normal. However, higher enzyme activities were observed in the blood of 11 schizophrenic patients (38-9 nmol/hr/ml RBC). Partially purified enzyme preparations from blood of normal and schizophrenic individuals were indistinguishable with respect to substrate specificities, isoelectric pH values, and ratios of the two O-methylated products. Therefore it is unlikely that any defect in O-methylation which may occur in schizophrenia can be attributed to a change in the intrinsic properties of erythrocyte catechol O-methyltransferase.

Adult↗