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PubMed2000

Molecular epidemiology of genetic polymorphisms in estrogen metabolizing enzymes in human breast cancer.

Epidemiologic studies indicate that most risk factors for breast cancer are related to reproductive and hormonal factors. For a number of years, the mechanism for estrogens in carcinogenesis was thought to be that of mitotic stimulation, with the growth promotion of ductal epithelial cells harboring precursor mutations in the breast. However, evidence is now available that estrogens may act as initiators of cellular alterations and tumorigenesis. Investigation and measurement of serum levels of estrogens in epidemiologic studies may, therefore, be misleading, because they may reflect levels quite different from those of hormone metabolites to which the target tissue is exposed. Proportions of hormone metabolites may be estimated by evaluation of associations between breast cancer risk and genetic polymorphisms in enzymes involved in hormone metabolism. A number of molecular epidemiologic studies have been conducted to evaluate associations between polymorphic genes involved in steroid hormone metabolism (i.e., CYP17, COMT, CYP1A1, CYP19, GST, and MnSOD) that may account for a proportion of enzymatic variability, and results are discussed in this review. There are strengths and limitations to such an approach, foremost of which may be the lack of insight into the extent to which individual variability in estrogen exposure may be explained by allelic variation. Variability in other endogenous and exogenous factors that impact parent hormones and their metabolites along activation and conjugation pathways may also affect associations in case-control comparisons. This and other possible reasons for inconsistencies in results of molecular epidemiologic studies are discussed. Contributions from population-based studies and those from the laboratory may together move this field ahead and more clearly elucidate the basis of hormonally related cancers, identifying etiologic factors and susceptible populations for preventive strategies.

Breast Neoplasms↗
PubMed1997

Methyl jasmonate induces an O-methyltransferase in barley.

We have previously described a truncated cDNA clone for a barley (Hordeum vulgare L. cv. Salome) jasmonate regulated gene, JRG5, which shows homology to caffeic acid O-methyltransferase (COMT). A cDNA encompassing the coding region was amplified by PCR and cloned for overexpression in E. coli. Western blot analyses indicate that the recombinant protein crossreacts with the antibodies directed against the tobacco class II OMT and only weakly with the antibodies for the tobacco class I OMT. An immunoreactive band in the protein extract of jasmonate-treated leaf segments suggests that JRG5 transcripts that accumulate after jasmonate treatment are also translated. Specific methylating activities on caffeic acid and catechol were obtained from the recombinant protein through renaturation of protein extracted from inclusion bodies or from bacteria grown and induced at low temperature. On Northern blots, the JRG5 transcripts were detected in the leaf sheath but not the leaf lamina; stem, root or inflorescence and accumulated in leaf segments after jasmonate application. Several hormone or stress treatments did not induce JRG5 mRNA accumulation. This includes sorbitol stress which is known to lead to enhanced endogenous jasmonate levels and the implications for jasmonate signaling are discussed. Based on quantitative measurements and fluorescence microscopy, jasmonate-induced accumulation of ferulic acid and phenolic polymers in the cell wall were detected and the possibility of cell wall strengthening mediated through phenolic crosslinks is discussed.

Acetates↗
PubMed2005

Volatile C6-aldehydes and Allo-ocimene activate defense genes and induce resistance against Botrytis cinerea in Arabidopsis thaliana.

Green leafy volatiles or isoprenoids are produced after mechanical wounding or pathogen/herbivore attacks in higher plants. We monitored expression profiles of the genes involved in defense responses upon exposing Arabidopsis thaliana to the volatiles. Among the genes investigated, those known to be induced by mechanical wounding and/or jasmonate application, such as chalcone synthase (CHS), caffeic acid-O-methyltransferase (COMT), diacylglycerol kinase1 (DGK1), glutathione-S-transferase1 (GST1) and lipoxygenase2 (LOX2), were shown to be induced with (E)-2-hexenal, (Z)-3-hexenal, (Z)-3-hexenol or allo-ocimene (2,6-dimethyl-2,4,6-octatriene). A salicylic acid-responsive gene, pathogenesis-related protein2 (PR2), was not induced by the volatiles. Detailed analyses of the expression profiles showed that the manner of induction varied depending on either the gene monitored or the volatile used. A chemically inert compound, (Z)-3-hexenol, was also potent, which suggested that chemical reactivity was not the sole requisite for the inducing activity. With a jasmonate-insensitive mutant (jar1), the induction by the volatiles was mostly suppressed, however, that of LOX2 was unaltered. An ethylene-insensitive mutant (etr1) showed responses almost identical to the wild type, with minor exceptions. From these observations, it was suggested that both the jasmonate-dependent and -independent pathways were operative upon perception of the volatiles, while the ETR1-dependent pathway was not directly involved. When Botrytis cinerea was inoculated after the volatile treatment, retardation of disease development could be seen. It appears that volatile treatment could make the plants more resistant against the fungal disease.

Acyclic Monoterpenes↗
PubMed2005

Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology.

It has been conventional for psychiatric research, including the search for predisposing genes, to proceed under the assumption that schizophrenia and bipolar disorder are separate disease entities with different underlying etiologies. These represent Emil Kraepelin's traditional dichotomous classification of the so-called "functional" psychoses and form the basis of modern diagnostic practice. However, findings emerging from many fields of psychiatric research do not fit well with this model. In particular, the pattern of findings emerging from genetic studies shows increasing evidence for an overlap in genetic susceptibility across the traditional classification categories-including association findings at DAOA(G72), DTNBP1 (dysbindin), COMT, BDNF, DISC1, and NRG1. The emerging evidence suggests the possibility of relatively specific relationships between genotype and psychopathology. For example, DISC1 and NRG1 may confer susceptibility to a form of illness with mixed features of schizophrenia and mania. The elucidation of genotype-phenotype relationships is at an early stage, but current findings highlight the need to consider alternative approaches to classification and conceptualization for psychiatric research rather than continuing to rely heavily on the traditional Kraepelinian dichotomy. As psychosis susceptibility genes are identified and characterized over the next few years, this will have a major impact on our understanding of disease pathophysiology and will lead to changes in classification and the clinical practice of psychiatry.

Bipolar Disorder↗
PubMed2005

The inheritance of intermediate phenotypes for schizophrenia.

PURPOSE OF REVIEW: While schizophrenia is substantially heritable, the mode of inheritance is complex, involving numerous genes of small effect and a non-trivial environmental component. The 'endophenotype' approach is an alternative method for measuring phenotypic variation that may facilitate the identification of susceptibility genes in the context of complexly inherited traits. Here we review recent studies applying this method to measures of brain structure, physiology, and function in samples of schizophrenia patients and their non-ill first-degree relatives (siblings and co-twins). RECENT FINDINGS: The results suggest that there are multiple heritable dimensions of central nervous system pathology in schizophrenia, including disturbances in the structure and functioning of frontal lobe systems involved in working memory and executive processes, temporal lobe systems involved in episodic memory, auditory perception, and language processing, and cortical and sub-cortical systems mediating smooth pursuit eye movements and sensorimotor gating. A number of genetic loci that are suspected to play a role in predisposing to schizophrenia, including the DISC1, COMT, neuregulin, dysbindin, and alpha-7 nicotinic receptor genes, appear to affect quantitative variation on one or more of these indicators. SUMMARY: Future work is encouraged to address whether each of these neural system dysfunctions are under the influence of a partially distinct set of genes, to elucidate the manner in which multiple genes may coalesce in determining schizophrenia-promoting dysfunction in each neurobehavioral domain, and to clarify the degree of overlap in these quantitative trait loci-endophenotype relationships with other forms of psychosis, particularly bipolar disorder.

Journal Article↗
PubMed1992

Effect of nitecapone and clorgyline, given intracerebro-ventricularly on L-dopa metabolism in the rat brain.

A new COMT inhibitor, nitecapone (OR-462) or clorgyline, a MAO-A inhibitor, was infused into the 3rd brain ventricle (i.c.v.) of conscious male rats. None of the enzyme inhibitors given alone alter hypothalamic or striatal levels of L-dopa, dopamine or their metabolites. Most of the rats were pretreated with levodopa/carbidopa (LD/CD, 15/30 mg kg-1 intraperitoneally). Now, the action of nitecapone is localized in the hypothalamus since homovanillic acid (HVA) is decreased there, not in the striatum. The levels of 3-O-methyldopa (3-OMD) are not changed in either brain region, suggesting a lack of the peripheral leakage of nitecapone. Clorgyline (3 and 10 micrograms rat-1) elevates hypothalamic and dopamine levels. Nitecapone and clorgyline decrease prolactin (PRL) levels below those reduced by LD/CD treatment.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

Association of the functional catechol-O-methyltransferase VAL158MET polymorphism with the personality trait of extraversion.

Across different personality theories, there is agreement that dopamine is the neurochemical basis of extraversion. However, evidence from molecular genetics for the validity of this hypothesis is far from convincing. The functional polymorphism of the catechol-O-methyltransferase gene (COMT VAL158MET) has not been related to extraversion before, although it is a promising candidate gene locus for extraversion because of its great influence on the catabolism of dopamine. In a sample of n=363 healthy study participants, the catechol-O-methyltransferase VAL158MET polymorphism was related to extraversion and novelty seeking.Results showed a significant association between catechol-O-methyltransferase, extraversion and the subscale exploratory excitement (NS1) of novelty seeking but not with the total novelty-seeking scale supporting the psychometric analyses of the personality scales. The findings support the hypothesis that the dopamine system is involved in positive emotionality and incentive motivation, which has implications for the understanding of the neurochemical correlates of normal and psychopathological behaviors.

Adult↗
PubMed1991

Reduction of circulating 3-O-methyldopa by inhibition of catechol-O-methyltransferase with OR-611 and OR-462 in cynomolgus monkeys: implications for the treatment of Parkinson's disease.

We studied the effectiveness of OR-611 and OR-462, two novel inhibitors of the enzyme catechol-O-methyltransferase (COMT), on 3-O-methyldopa (OMD) formation in cynomolgus monkeys following intravenous levodopa administration. OR-611 dose-dependently reduced the area under the OMD concentration-vs-time curve, reduced maximum plasma OMD concentrations, delayed the time to peak OMD levels, reduced systemic levodopa clearance, and prolonged the elimination half-life of levodopa. Similar effects on peripheral levodopa metabolism were seen with doses of 15 mg/kg of OR-611 and OR-462, its sister compound, which lacks the ability to penetrate the central nervous system (CNS).

Animals↗
PubMedDate not supplied

Pharmacokinetics and pharmacodynamics of L-Dopa after acute and 6-week tolcapone administration in patients with Parkinson's disease.

Tolcapone, a central and peripheral catechol O-methyltransferase (COMT) inhibitor, reduces the conversion of L-Dopa into 3-O-methyl-Dopa (3-OMD), thus leading to more stable and sustained L-Dopa plasma levels. This study was designed to evaluate the effects of acute and 6-week tolcapone administration on L-Dopa pharmacokinetics and pharmacodynamics in Parkinson's disease (PD) patients with predictable motor fluctuations. Tapping test, walking time, and tremor, as well as L-Dopa and 3-OMD plasma levels, were assessed before and for 5 hours after the administration of a single L-Dopa dose, alone or in combination with 200 mg tolcapone, in seven patients with PD. This clinical and pharmacokinetic study was repeated after 6 weeks of tolcapone therapy (200 mg three times daily). It was observed that tolcapone, after both acute and chronic administration, prolonged the motor improvement induced by L-Dopa. As a result, at week 6 of tolcapone therapy, the daily hours spent "off" were significantly decreased. Tolcapone significantly increased the area under the curve of L-Dopa plasma levels by slowing down the elimination of L-Dopa from plasma, whereas the maximal concentration of L-Dopa was not modified. 3-OMD levels decreased significantly after acute tolcapone administration, and after 6 weeks of tolcapone therapy, they were approximately one sixth of pre-tolcapone values. The data confirm that tolcapone decreases L-Dopa clearance and prolongs motor response in PD patients with motor fluctuations, and that this effect is maintained after 6 weeks of tolcapone therapy.

Antiparkinson Agents↗
PubMedDate not supplied

A comparison of dopamine agonists and catechol-O-methyltransferase inhibitors in Parkinson's disease.

To compare the efficacy and tolerability of three dopamine agonists--pergolide (PRG), pramipexole (PRX), and ropinirole (ROP)-and two catechol-O-methyltranferase (COMT) inhibitors-tolcapone (TOL) and entacapone (ENT)-as add-on therapies to levodopa (L-Dopa) in Parkinson's disease, we analyzed randomized, double-blind, placebo-controlled, multicenter studies. To our knowledge, they had not yet been evaluated in comparison with each other. Statistical analyses used odds ratios, numbers needed to harm, and Fisher's inverse chi2 method. Seven studies meeting the inclusion criteria included treatment of 1,756 patients. The common efficacy measures were the reduction of L-Dopa dose and "off' duration. The reported reduction in L-Dopa dose was significant for all drugs in relation to placebo, but was most significant for PRX and ENT (p < 0.0001). The most significant reduction in "off' duration was with PRG, PRX, and ENT (p < 0.001). The common tolerability measures were the percentage of patients withdrawn because of side effects, because of any reason, and because of the development of dyskinesias. Ropinirole, PRX, and ENT caused fewer withdrawals related to side effects. Pergolide was better than other analyzed drugs concerning withdrawals for any reason. All drugs caused more dyskinesias than placebo (p < 0.0001), with overlapping confidence intervals, except for TOL 600 mg, which caused more dyskinesias than dopamine agonists and ENT. Pramipexole and ENT had the best efficacy and tolerability profile in this analysis.

Catechol O-Methyltransferase Inhibitors↗
PubMedDate not supplied

Impact of gastric emptying on levodopa pharmacokinetics in Parkinson disease patients.

Adjunction of the catechol-O-methyltransferase (COMT) inhibitor entacapone (EN) to levodopa/carbidopa (LD/CD) improves motor symptoms in patients with Parkinson disease (PD) by a prolonged elimination of LD. But it is not known whether EN addition influences gastric emptying and thus LD pharmacokinetics and pharmacodynamics. Objectives were to simultaneously determine plasma LD elimination, gastric emptying, and clinical response after a single intake of the same LD dosage as LD/CD--or as (LD/CD/EN) formulation on 2 consecutive days. In both groups, PD patients with delayed gastric emptying had significant lower LD plasma concentrations. Addition of EN did not influence gastric emptying but significantly improved motor response, which was not different for patients with delayed gastric emptying. However, with and without EN adjunction gastric emptying distinctly contributes to the variability of plasma LD bioavailability. This may impact LD delivery to the brain and thus motor response in PD patients. Therefore, fine tuning of LD application, which considers gastric emptying, becomes more and more essential in advanced PD stages with a reduced striatal neuronal dopamine capacity, which is responsible for maintenance of motor response in early PD patients.

Adult↗
PubMed1996

Fluorodopa positron emission tomography with an inhibitor of catechol-O-methyltransferase: effect of the plasma 3-O-methyldopa fraction on data analysis.

Flurodopa (FDOPA) is an analogue of L-di-hydroxyphenylalanine (L-dopa) used to assess the nigrostriatal dopamine system in vivo with positron emission tomography (PET). However, FDOPA/PET quantitation is complicated by the presence of the 3-O-methyl-FDOPA (3OMFD) fraction in brain and plasma. Pretreatment with entacapone (OR-611), a peripheral catechol O-methyl-transferase (COMT) inhibitor, greatly reduces the plasma 3OMFD fraction and provides an ideal situation to evaluate the contribution of the plasma 3OMFD fraction in several kinetic models of FDOPA uptake. We performed FDOPA/PET with and without the OR-611 preadministration in six Parkinson's disease (PD) patients. We measured the time-course of the plasma FDOPA and 3OMFD fractions using high-pressure liquid chromatography (HPLC). We calculated striato-occipital ratios (SOR), and estimated the striatal FDOPA uptake rate constant graphically using the plasma FDOPA and occipital tissue time activity curves (KiFD and KiOCC, respectively). We also estimated striatal dopa decarboxylase (DDC) activity (k3D) using a model incorporating independent measurements of 3OMFD transport kinetic rate constants. With the preadministration of OR-611, the pharmacological efficiency in plasma was prolonged significantly (21.1-37.7%; p < 0.01). We also observed significant mean elevations in SOR and KiOCC by 21.8 and 53.5%, respectively (p < 0.05). KiFD and k3D did not show significant change. We conclude that OR-611 prolongs the circulation time of FDOPA in the plasma but does not alter rate constants for striatal FDOPA uptake or decarboxylation.

Adult↗
PubMed1998

Influence of 0.1 or 0.2% cholesterol-enriched diets on the induction of atherosclerosis and aorta reactivity in vitro.

Current knowledge of atherogenesis is largely based on animal models of hypercholesterolemia, which rarely show changes similar to the lesions described in humans. We studied the influence of two low cholesterol-enriched diets on the development of anatomopathologic lesions and on the reactivity of the isolated aorta in rabbits. Compared with controls (rabbits fed a normal diet), a 0.1% cholesterol-enriched diet over a 6- or 9-month period produced increases of the 5-hydroxytryptamine (5-HT)-induced contractile responses, as well as a decreases in acetylcholine (ACh)-induced relaxing response (endothelium-dependent, through the production of NO). Noradrenaline (NA)-induced contractions and relaxations elicited by sodium nitroprusside (SNP; endothelium independent) were not significantly modified. Because at 6 months, significant anatomopathologic intimal early lesions were not found, functional endothelial changes can explain such findings. There was a defect in NO synthesis, release, or diffusion; 5 HT, but not NA, may be responsible for inducing NO production. In 0.2% cholesterol-fed rabbits at 4 and 12 weeks, increases of 5-HT- and NA-induced contractile responses were found. In both cases, there was a decrease of ACh-induced relaxing effect, whereas responses to SNP remained unchanged. Intimal early and advanced lesions were present at both the 4- and 12-week periods. These data suggest abnormalities of the NO system. The effects obtained with NA may be explained by a possible decrease of catechol-O-methyltransferase (COMT) or monoamine oxidase (MAO) activities or both or by decreased amine uptake. The extent to which NA may induce NO production is small, because changes in NA-induced contractions are verified only in the presence of significant alterations in the endothelium. The use of a 0.2% cholesterol diet for a short time may induce atherosclerotic lesions, whereas the 0.1% cholesterol diet for a 9-month period, besides being closer to the human diet, allows the detection of functional abnormalities before the evidence of structural lesions.

Animals↗
PubMed1984

Some important epochs in medicine.

One of the problems in attempting to chronicle briefly the great moments in the history of medicine is that, like the healing process itself, turning points are difficult to pinpoint. There have been surprisingly few "eurekas." In addition, unlike the history of corporate bodies or institutions (such as the church and the nation state) there is no continuous record, no deliberate account. However, the lack of such systemic recording has had its advantage in excluding the element of mythology and myopic partisanship. Since we must choose some kind of framework, we have (in addition to the arbitrary division into Ancient, Medieval, Modern Renaissance, and Enlightenment periods) taken a page from the works of August Comte, the eminent 19th Century philosopher, who divided all of history into three states: theologic (fictional), metaphysical (abstract), and scientific (positivistic). The division is convenient because it not only demonstrates the timelessness and transcendence of medicine, but it also makes it obvious that the cyclic nature of medical interests continues, even today, to offer a theologic, metaphysical, and scientific approach to the problems of health care.

Chemistry↗
PubMed2004

Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition.

MDMA (3,4-methylenedioxymethamphetamine, ecstasy) is a widely misused psychostimulant drug abused among large segments of the young population. Pharmacologically it displays effects related to amphetamine-type drugs and a set of distinctive effects (closeness to others, facilitation to interpersonal relationship, and empathy) that have been named by some authors "entactogen" properties. MDMA is a potent releaser and/or reuptake inhibitor of presynaptic serotonin (5-HT), dopamine (DA), and norepinephrine (NE). These actions result from the interaction of MDMA with the membrane transporters involved in neurotransmitter reuptake and vesicular storage systems. The most frequent effects after MDMA/ecstasy administration are euphoria, well-being, happiness, stimulation, increased energy, extroversion, feeling close to others, increased empathy, increased sociability, enhanced mood, mild perceptual disturbances, changed perception of colors and sounds, somatic symptoms related to its cardiovascular and autonomic effects (blood pressure and heart rate increase, mydriasis), and moderate derealization but not hallucinations. Acute toxic effects are related to its pharmacologic actions. The serotonin syndrome (increased muscle rigidity, hyperreflexia, and hyperthermia), among others, is characteristic of acute toxicity episodes. MDMA metabolism is rather complex and includes 2 main metabolic pathways: (1) O-demethylenation followed by catechol-O-methyltransferase (COMT)-catalyzed methylation and/or glucuronide/sulfate conjugation; and (2) N-dealkylation, deamination, and oxidation to the corresponding benzoic acid derivatives conjugated with glycine. The fact that the polymorphic enzyme CYP2D6 partially regulates the O-demethylenation pathway prompted some expectations that subjects displaying the poor metabolizer phenotype may be at higher risk of acute toxicity episodes. In this metabolic pathway a mechanism-based inhibition of the enzyme operates because the formation of an enzyme-metabolite complex that renders all subjects, independently of genotype, phenotypically poor metabolizers after the administration of 2 consecutive doses. Therefore, the impact of CYP2D6 pharmacogenetics on acute toxicity is limited. One of the interesting features of MDMA metabolism is its potential involvement in the development of mid- to long-term neurotoxic effects as a result of progressive neurodegeneration of the serotonergic neurotransmission system.

Adrenergic Uptake Inhibitors↗
PubMed2000

Association between polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers.

Central dopaminergic reward pathways give rise to dependence and are activated by nicotine. Allelic variants in genes involved in dopamine metabolism may therefore influence the amount of tobacco consumed by smokers. We developed assays for polymorphisms in dopamine beta-hydroxylase (DBH), monoamine oxidase (MAO) and catechol O-methyl transferase (COMT) using the polymerase chain reaction with sequence specific primers (PCR-SSP). We then typed 225 cigarette smokers to assess whether genotype was related to the number of cigarettes smoked a day. Smokers with DBH 1368 GG genotype smoked fewer cigarettes than those with GA/AA [mean difference -2.9 cigarettes, 95% confidence interval (CI) -5.5, -0.4; P = 0.022]. The effect reached statistical significance in women (-3.8, 95% CI -6.4, -1.0, P = 0.007) but not in men (-1.5, 95% CI -6.0, 3.0, P = 0.498). Overall, the effect was greater when analysis was confined to Caucasians (-3.8, 95% CI -6.6, -1.1, P = 0.007). Smokers with MAO-A 1460 TT/TO smoked more cigarettes than those with CC/CT/CO (2.9, 95% CI 0.6, 5.1, P = 0.013). Within each sex group, the trend was similar but not statistically significant (difference for men 2.9, 95% CI -1.0, 6.7; for women 2.0, 95% CI -0.7, 4.8). The effect of the allele was greater in smokers with a high body mass index (> 26) (difference 5.1, 95% CI 1.4, 8.8, P = 0.008). More heavy smokers (> 20 a day) had the DBH 1368A allele when compared to light smokers (< 10 a day). (Relative risk 2.3, 95% CI 1.1, 5.0, P = 0.024.) The trend for increasing prevalence of the DBH A allele in heavy smokers was greater when analysis was restricted to Caucasians (relative risk 3.2, 95% CI 1.3, 8.2, P = 0.004). Conversely, heavy smokers were less likely to have the MAO-A 1460C allele (relative risk 0.3, 95% CI 0.1, 0.7, P = 0.012). Variations in DBH and MAO predict whether a person is a heavy smoker and how many cigarettes they consume. Our results support the view that these enzymes help to determine a smoker's requirement for nicotine and may explain why some people are predisposed to tobacco addiction and why some find it very difficult to stop smoking. This finding has important implications for smoking prevention and offers potential for developing patient-specific therapy for smoking cessation.

Adult↗
PubMed2005

Association study of catechol-O-methyltransferase gene polymorphism in Korean male alcoholics.

OBJECTIVE: Catechol-O-methyltransferase, which has a functional genetic polymorphism, plays an important role in dopamine metabolism. The study analyzed the association between the catechol-O-methyltransferase gene polymorphism and alcohol dependence in the Korean population. METHODS: Ninety-seven male alcoholics and 94 male age-matched normal controls were enrolled in this study. Polymerase chain reaction-based genotyping was used to verify the presence of the catechol-O-methyltransferase gene polymorphism. The patients were divided into two subtypes (violent group and non-violent group) according to their history of violent behavior. RESULTS: No difference in the distribution of the catechol-O-methyltransferase genotypes (H/H, H/L, L/L) and alleles (H, L) was observed between the patients and the controls. However, the differences between the violent and non-violent groups were significant in terms of the frequencies of the COMT genotypes (chi=7.977, df=2, P=0.019) and the alleles (chi=6.832, df=1, P=0.012). In addition, significant differences in the frequencies of the catechol-O-methyltransferase allele (chi=4.481, df=1, P=0.040) were observed between the non-violent group and the controls. CONCLUSIONS: This suggests that the catechol-O-methyltransferase gene polymorphism is not associated with the development of alcohol dependence, but may affect the susceptibility to a clinical heterogeneity of alcohol dependence, at least in the Korean population.

Alcoholism↗
PubMed2005

A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of colorectal cancer.

OBJECTIVES: Sporadic colorectal cancer (CRC) is considered a multifactorial disease where multiple exposures interact with the individual genetic background resulting in risk modulation. We performed an association study aimed to investigate the role of single nucleotide polymorphisms (SNPs) within genes of phase I (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2D6, CYP2E1, CYP2C9, CYP2C19, CYP3A4, ADH2, EPHX1) and phase II of the xenobiotic metabolism (ALDH2, COMT, GSTA2, GSTA4, GSTM1, GSTM3, GSTP1, GSTT2, MTHFR, NAT1, NAT2, NQO1, MnSOD2, SULT1A1, TPMT). METHODS: We genotyped 377 cases and 326 controls, by use of an oligonucleotide micro-array and the arrayed primer extension technique (APEX). RESULTS: N-acetyl-transferase 1 'rapid' phenotype and CYP1A2 -164C>A carriers were associated with increased risk of CRC, confirming data reported in previous studies. Interestingly, homozygotes for allele 48G within CYP1B1, a variant with an increased activity towards several substrates including sex hormones, were at increased risk (OR=2.81, 95% CI 1.32-5.99). Moreover, CYP1A1 SNPs T461N and -1738A>C were associated with a reduced risk of cancer (OR=0.52; 95% CI 0.31-0.88 and OR=0.69, 95% CI 0.50-0.94 for carriers, respectively). CONCLUSIONS: The present data suggest a role for CYP1B1 and CYP1A1 as new candidate genes in the etiology of CRC and confirm the carcinogenic role of aromatic amines metabolism for colorectum.

Case-Control Studies↗