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PubMed2005

Catechol-O-methyltransferase and monoamine oxidase B genes and susceptibility to sporadic Parkinson's disease in a Polish population.

Recent reports have proved that genetic factors play a role in the pathogenesis of sporadic Parkinson's disease (PD). It has been suggested that polymorphisms in monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) might increase the risk of PD. A total of 210 Polish patients with sporadic PD and 152 healthy controls were studied. The MAOB and COMT polymorphisms were identified using the polymerase chain reaction-restriction fragment length polymorphism method. The MAOB allele and genotype frequencies in PD patients did not differ significantly from the controls. A statistically lower frequency of the COMTLL genotype in patients with parkinsonism was found. The combined haplotype of the MAOB G (G/G) and COMTHL genotype showed a fourfold increase (p < 0.05) in the risk of PD in female patients in this Polish population.

Adult↗
PubMed1997

Emerging treatments in Parkinson's disease.

This paper provides a critical review on the most recent developments in the treatment of Parkinson's disease. New symptomatic therapies include the use of catechol-O-methyltransferase (COMT) inhibitors, new dopamine agonists and of surgical treatments (such as pallidotomy or deep brain stimulation). Protective strategies include the use of COMT and monoamine oxidase B inhibitors, of dopamine agonists and of trophic factors. The main preclinical premises, on which the usage of newly developed therapies is based, are discussed. Symptomatic therapy has been greatly refined in recent years and has gradually become a polytherapeutic approach. Protective therapy, which will attract the interest of fundamental and clinical research in the field of Parkinson's disease, is the real future challenge.

Antiparkinson Agents↗
PubMed1977

Platelet monoamine oxidase in women with premenstrual syndrome.

Platelet monoamine oxidase (MAO) and RBC catechol-O-methyltransferase (COMT) were studied in 12 women suffering from premenstrual syndrome. No significant variation of platelet MAO or RBC COMT was found during the menstrual cycle, as opposed to previous studies on normal women and monkeys, which report a significant decline of platelet MAO activity in the 5-day period before menses.

Adult↗
PubMed1977

Effect of chronic denervation on the activities of monoamine oxidase and catechol-O-methyl transferase and on the contents of noradrenaline and adenosine triphosphate in the rabbit ear artery.

When assayed on homogenates of the rabbit ear artery up to 192 h after sympathetic denervation, the activity of monoamine oxidase (MAO) showed a small but significant decrease (maximum 9%). The activity of catechol-O-methyl transferase (COMT) appeared unchanged, although it is possible that the small and variable nature of this enzyme activity compared with that of MAO may have masked a comparable effect of denervation. The maximum decreases in noradrenaline (NA) and adenosine triphosphate (ATP) contents were greater than 90% at 48 h, and 32% at 96 h after denervation. These results confirm the presence of neuronal as well as extra-neuronal MAO, and also the presence of extraneuronal comt in this artery. The decline in ATP contents after denervation suggest that part of the ATP is neuronal. However, the estimated ratio of NA to neuronal ATP is far in excess of that reported for isolated noradrenaline storage vesicles, suggesting that the major portion of the neuronal ATP was not present in these vesicles.

Adenosine Triphosphate↗
PubMed1981

Effect of moderate cooling on adrenergic neuroeffector interaction in canine cutaneous veins.

Experiments were performed to investigate the effect of moderate cooling on adrenergic neuroeffector interaction in canine cutaneous veins. Helical strips of dog's saphenous vein, untreated or first incubated with 3H-norepinephrine were mounted for superfusion and isometric tension recording; the overflow of endogenous catecholamines or 3H-norepinephrine and its metabolites, respectively, were measured in the superfusate. In other experiments the monoamine oxidase activity or the catechol-O-methyltransferase (COMT) activity of the saphenous vein wall was determined. Moderate cooling (from 37 to 24 degree C) decreased the evoked release of endogenous norepinephrine during electrical stimulation of the adrenergic nerve endings in the blood vessel wall. Moderate cooling depressed the overflow of 3H-norepinephrine and its metabolites in unstimulated preparations, during electrical stimulation during superfusion with high K+ solution and during exposure to tyramine. Moderate cooling reduced the activity of monoamine oxidase significantly more than that of COMT. The relative alterations in overflow of norepinephrine and its metabolites caused by a same degree of cooling in basal conditions and during the different forms of increased overflow of adrenergic transmitter suggest that lowering the temperature inhibits the exocytotic process, but at the same time slows down the diffusion of norepinephrine from the junctional cleft to the extracellular space to the extent that during sympathetic nerve stimulation at 24 degree C the effective junctional concentration of the transmitter may be comparable to that obtained at 37 degree C. The inhibitory effect of moderate cooling on the extraneuronal metabolism of norepinephrine appears to affect little the effective junctional concentration of the adrenergic transmitter.

Adrenergic Fibers↗
PubMed1983

Effect of inhibitors of neuronal and extraneuronal uptake on the accumulation and metabolism of 3H-l-norepinephrine in rabbit aorta.

In the isolated adventitia of rabbit aorta, blockade of neuronal uptake decreased the accumulation and deamination of 3H-l-norepinephrine (3H-l-NE) whereas blockade of extraneuronal uptake decreased O-methylation. Thus most of the O-methylation occurs in the extraneuronal elements. In the isolated media, blockade of extraneuronal uptake decreased metabolism but not accumulation of 3H-l-NE. If NE metabolism was prevented by pretreatment with pargyline and U-0521, 3H-l-NE accumulation in the isolated media increased markedly and now inhibitors of extraneuronal uptake could decrease this accumulation of 3H-l-NE by the isolated media. Thus when MAO and COMT are intact, NE does not accumulate in the extraneuronal compartment containing these enzymes, probably because it is metabolized as fast as it enters the compartment. Since the level of 3H-l-NE in the isolated media exceeded the sorbitol space when MAO and COMT are intact, some 3H-l-NE must have accumulated in a compartment which does not contain these enzymes.

Animals↗
PubMed1983

[Adrenal catecholamines and their metabolism in the vitamin A deficient rat].

The adrenal catecholamines (norepinephrine and epinephrine) and their conversion enzymes (PNMT, COMT) were comparatively investigated in: (1) rats fed a diet deprived of vitamin A, inducing a rapid and severe deficiency; (2) rats fed another diet leading to a more progressive deficiency (rats supplemented with retinol served as controls for these two types of diet), and (3) rats fed a whole industrial diet. The first diet induced a strong accumulation of adrenal catecholamines and increased the activity of PNMT and COMT. The second diet only increased the adrenal content of norepinephrine and epinephrine.

Adrenal Medulla↗
PubMed1991

Catecholamine metabolic pathways and exercise training. Plasma and urine catecholamines, metabolic enzymes, and chromogranin-A.

BACKGROUND: Because acute exercise increases systemic catecholamines, we sought to determine whether exercise training would alter daily or exercise-related catecholamine release and inactivation. METHODS AND RESULTS: In 24-hour urine collections, catecholamines and metabolites provided indexes of overall oxidative deamination, sulfation, and O-methylation. Plasma catecholamines, the sulfoconjugates of each, and chromogranin-A were determined at rest and during exercise in 10 well-trained male subjects and nine minimally trained male subjects (maximal oxygen uptake 55.2 and 42.5 ml/kg/min, respectively), and levels of activities of catechol-O-methyltransferase (COMT), monoamine oxidase B (MAO-B), and thermolabile phenolsulfotransferase (TL-PST) were also determined. Plasma-free catecholamines showed minimal differences between the two groups at submaximal exercise (4 minutes) but large differences at maximal exercise, reflecting the different exercise levels attained. Inactivation of plasma catecholamines by sulfation across rest and exercise tended to be greater in the well-trained group, with small increases in both plasma sulfoconjugated dopamine and sulfoconjugated norepinephrine. In the well-trained group, urinary metabolites demonstrated trends toward increased dopamine release (p less than 0.07) and small increases in the daily release of epinephrine and its sulfoconjugated metabolites. Indexes of deamination, sulfoconjugation, and O-methylation, with the exception of a reduced deamination of dopamine and the activities of COMT, MAO-B, and TL-PST were not different in the two groups. CONCLUSIONS: Despite considerable differences in the exercise activities per week between well-trained and minimally trained individuals, there were minimal differences in the release and metabolism of catecholamines at rest or during exercise.

Adult↗
PubMedDate not supplied

Role of catecholamine degradative enzymes and the adrenergic innervation in determining the cerebrovascular response to infused norepinephrine.

Cerebral blood flow responses to intra-arterial infusion of norepinephrine (NE) at 0.55 microgram/kg/min and 1.1 microgram/kg/min were studied in 3 groups of baboons. The flow was measured by the intracarotid 133xenon clearance technique using a computer program to calculate flow (height over area--H/A) flow (initial slope--is) and cerebral metabolic utilization of oxygen (CMRO2). The normal response to NE was to increase flow without significant changes in CMRO2. Blockade of catechol-o-methyl transferase (COMT) produced vasoconstrictor responses to these same NE doses. Monoamine oxidase blockade abolished the normal vasodilation. Denervation of the cerebral circulation with intracisternal 6-hydroxydopamine produced vasoconstrictor responses with flow (H/A) but not with flow (is). It is concluded that the extra-neuronal COMT enzyme is important in limiting the access of blood-borne NE to cerebrovascular constrictor receptors.

Adrenergic Fibers↗
PubMed1979

The role of plasma amine oxidase, platelet monoamine oxidase, and red cell catechol-O-methyl transferase in severe behavioral reactions to disulfiram.

The authors assayed platelet monoamine oxidase (MAO), plasma amine oxidase (AO), and red cell catechol-O-methyl transferase (COMT) in 32 male alcoholics before they began disulfiram treatment. Seven subjects developed psychotic reactions to disulfiram; these 7 had significantly lower pretreatment MAO and AO levels and significantly higher COMT than the patients who had no adverse reactions to disulfiram, which suggests that severe behavioral reactions to disulfiram are associated with differences in enzyme activities.

Adolescent↗
PubMed1982

Biochemical differences in children with conduct disorder socialized and undersocialized.

The authors compared plasma dopamine beta-hydroxylase (DBH), platelet monoamine oxidase (MAO), whole blood serotonin, and RBC catechol O-methyltransferase (COMT) in 25 children with conduct disorder and 20 control children. They found that children diagnosed as having conduct disorder undersocialized had significantly lower DBH activity than children diagnosed as having conduct disorder socialized and the control group. The children with conduct disorder socialized had significantly higher COMT activity than the other two groups. When children with a diagnosis of conduct disorder plus a diagnosis of attention deficit disorder were compared with the control group, no significant biochemical differences were found because of the mixing of the two diagnoses.

Attention Deficit Disorder with Hyperactivity↗
PubMed1984

Amish study, V: Lithium-sodium countertransport and catechol O-methyltransferase in pedigrees of bipolar probands.

The authors studied 87 individuals from four large Amish pedigrees to determine the relationship between susceptibility to affective disorders and variation in the measures of two biochemical variables, catechol O-methyltransferase (COMT) and lithium countertransport. Assays were done in duplicate and blind to diagnostic or pedigree status. Data were analyzed separately within families as well as by pooling ill and well subjects across pedigrees. Various statistical analyses yielded no significant differences in lithium measures or COMT activity levels between members diagnosed as having a form of affective disorder and the normal members.

Bipolar Disorder↗
PubMed2003

Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies.

OBJECTIVE: There is strong evidence for a genetic contribution to schizophrenia, but efforts to identify susceptibility genes have been largely unsuccessful because of the low power of individual studies. The authors' goal was to evaluate the collective evidence for an association between the Val158/108Met polymorphism of the catechol O-methyltransferase (COMT) gene and schizophrenia. METHOD: They performed separate meta-analyses of existing case-control and family-based association studies. RESULTS: Overall, case-control studies showed no indication of an association between either allele and schizophrenia, and family-based studies found modest evidence implicating the Val allele in schizophrenia risk. The pooled analyses of studies from diverse geographical regions may have obscured ethnic differences in patterns of genetic risk for schizophrenia. Stratification of the studies by ethnicity of the subjects yielded evidence for an association with the Val allele in case-control studies of European samples and, especially, in family-based studies of European samples. Case-control and family-based studies of Asian samples produced mixed results and, overall, little evidence for association. CONCLUSIONS: The results of the two types of association studies diverged somewhat, but the evidence from the family-based studies, although based on fewer reports, may be more accurate. The Val allele may be a small but reliable risk factor for schizophrenia for people of European ancestry, but the influence of this polymorphism on risk in Asian populations remains unclear. These results call for more family-based studies to confirm the association between COMT and schizophrenia in European samples and to clarify its contribution to risk in Asian samples. They also suggest that case-control studies should use methods of genomic control to avoid being confounded by population stratification.

Adult↗
PubMed2006

SNP-SNP interactions in breast cancer susceptibility.

BACKGROUND: Breast cancer predisposition genes identified to date (e.g., BRCA1 and BRCA2) are responsible for less than 5% of all breast cancer cases. Many studies have shown that the cancer risks associated with individual commonly occurring single nucleotide polymorphisms (SNPs) are incremental. However, polygenic models suggest that multiple commonly occurring low to modestly penetrant SNPs of cancer related genes might have a greater effect on a disease when considered in combination. METHODS: In an attempt to identify the breast cancer risk conferred by SNP interactions, we have studied 19 SNPs from genes involved in major cancer related pathways. All SNPs were genotyped by TaqMan 5'nuclease assay. The association between the case-control status and each individual SNP, measured by the odds ratio and its corresponding 95% confidence interval, was estimated using unconditional logistic regression models. At the second stage, two-way interactions were investigated using multivariate logistic models. The robustness of the interactions, which were observed among SNPs with stronger functional evidence, was assessed using a bootstrap approach, and correction for multiple testing based on the false discovery rate (FDR) principle. RESULTS: None of these SNPs contributed to breast cancer risk individually. However, we have demonstrated evidence for gene-gene (SNP-SNP) interaction among these SNPs, which were associated with increased breast cancer risk. Our study suggests cross talk between the SNPs of the DNA repair and immune system (XPD-[Lys751Gln] and IL10-[G(-1082)A]), cell cycle and estrogen metabolism (CCND1-[Pro241Pro] and COMT-[Met108/158Val]), cell cycle and DNA repair (BARD1-[Pro24Ser] and XPD-[Lys751Gln]), and within carcinogen metabolism (GSTP1-[Ile105Val] and COMT-[Met108/158Val]) pathways. CONCLUSION: The importance of these pathways and their communication in breast cancer predisposition has been emphasized previously, but their biological interactions through SNPs have not been described. The strategy used here has the potential to identify complex biological links among breast cancer genes and processes. This will provide novel biological information, which will ultimately improve breast cancer risk management.

Adult↗
PubMed2006

Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post-surgical pain in humans.

BACKGROUND: Candidate gene studies on the basis of biological hypotheses have been a practical approach to identify relevant genetic variation in complex traits. Based on previous reports and the roles in pain pathways, we have examined the effects of variations of loci in the genes of monoamine neurotransmitter systems including metabolizing enzymes, receptors and transporters on acute clinical pain responses in humans. RESULTS: Variations in the catecholamine metabolizing enzyme genes (MAOA and COMT) showed significant associations with the maximum post-operative pain rating while the serotonin transporter gene (SLC6A4) showed association with the onset time of post-operative pain. Analgesic onset time after medication was significantly associated with the norepinephrine transporter gene (SLC6A2). However, the association between COMT genetic variation and pain sensitivity in our study differ from previous studies with small sample sizes, population stratification and pain phenotype derived from combining different types of pain stimuli. Correcting for multiple comparisons did not sustain these genetic associations between monoamine neurotransmitter systems and pain sensitivity even in this large and homogeneous sample. CONCLUSION: These results suggest that the previously reported associations between genetic polymorphisms in the monoamine neurotransmitter systems and the interindividual variability in pain responses cannot be replicated in a clinically relevant pain phenotype.

Acute Disease↗
PubMed2002

Genetic determinants of mammographic density.

BACKGROUND: Changes in breast density are highly correlated with steroid hormone exposure. MATERIALS AND METHODS: In a cross-sectional study of 396 Caucasian and African-American women, we evaluated whether polymorphisms in genes involved in steroid hormone biosynthesis and metabolism, CYP17 (T27C), COMT (Val158Met), 17HSDB1 (Ser312Gly) and 3HSDB1 (Asn367Thr), predict mammographic density. We also evaluated whether associations vary by menopausal and hormone replacement therapy status. RESULTS: We found no strong consistent relationships between polymorphisms in these genes and breast density. African-American women homozygous for the Thr allele of 3HSDB1 had increased density (the absolute difference versus the Asn/Asn genotype was +19.7%; P trend = 0.02), while Caucasian homozygous women had decreased density (-5.1%; P trend = 0.04). Among premenopausal women, carriers of the Ser allele had (not significantly) greater density (versus Gly/Gly genotype: +7.1%; P trend = 0.07). In addition, among current users of hormone replacement therapy, we observed that women with the low-activity Met/Met genotype of COMT had greater breast density (versus the Val/Val genotype: +11.7%; P trend = 0.01). CONCLUSION: Additional large studies evaluating these and other candidate breast cancer genes will be required to determine what proportion, if any, of the interindividual differences in breast density are due to underlying genetic variation in genes involved in steroid hormone biosynthesis or metabolism.

17-Hydroxysteroid Dehydrogenases↗
PubMed2001

Aggressive behaviour in patients with schizophrenia is associated with catechol-O-methyltransferase genotype.

BACKGROUND: Evidence exists for an association between aggression and schizophrenia. Although the aetiology of aggression is multifactorial, three studies have reported associations between polymorphisms of the catechol-O-methyltransferase (COMT) gene and aggression in schizophrenia. AIMS: To replicate these findings in a larger sample using the Overt Aggression Scale (OAS). METHOD: A sample of 180 people with DSM-IV schizophrenia were rated for aggression using the OAS. Kruskal-Wallis and contingency table analyses were applied to the OAS results. RESULTS: The high-activity homozygotes showed significantly higher scores of aggression, whereas the heterozygotes showed significantly lower scores. The odds ratio for aggression for the high-activity homozygotes was 2.07 (95% Cl=1.03-4.15), whereas that for the heterozygotes was 0.54 (95% Cl=0.30-1.00). CONCLUSIONS; The high-activity COMT homozygote confers a higher risk of recorded aggression in schizophrenia. Heterozygotes had a significantly lower risk, which may represent an example of heterosis/heterozygote advantage.

Aggression↗
PubMed2003

Estrogen-metabolizing gene polymorphisms, but not estrogen receptor-alpha gene polymorphisms, are associated with the onset of menarche in healthy postmenopausal Japanese women.

Both onset and cessation of menstruation have strong genetic inclination. We aimed to identify genetic factors influencing the onset of menarche and natural menopause in a Japanese population by investigating the polymorphisms of estrogen receptor-alpha and estrogen-metabolizing enzyme genes. Three hundred seventeen postmenopausal Japanese women, aged 46 yr and over, were enrolled in this study under informed consent. Genomic DNA was extracted from peripheral leukocytes, and PCR-based restriction fragment length polymorphism assays were used to determine estrogen receptor-alpha: PvuII, XbaI, and estrogen-metabolizing enzymes; CYP17, estrogen biosynthesis (high activity, A2/A2, CYP1A1), hydroxylation (high inducibility, vt/vt, and COMT), inactivation (low activity, L/L) genotypes. There were no significant differences in ages at menarche and natural menopause or years of menstruation among each PvuII or XbaI genotype and seven combinations of PvuII and XbaI genotypes. We found that ages at menarche in women with A1/A2 (higher activity of CYP17; 13.6 +/- 1.2 yr) were significantly earlier than in those with A1/A1 (lower activity of CYP17; 14.1 +/- 1.3 yr). There were no significant differences in age at natural menopause and years of menstruation among each CYP17, CYP1A1, or COMT genotype. The small sample size of each combination of estrogen-metabolizing genotypes made it impractical to evaluate the effects of the interdependency of each genotype, including extreme genotype categories such as A2/A2L/Lvt/vt vs. A1/A1H/Hwt/wt genotypes, on ages at menarche and/or natural menopause. The results suggest that the estrogen-metabolizing CYP17 genotype influences age at menarche in healthy postmenopausal Japanese women.

Aged↗