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PubMed2005

Does lignin modification affect feeding preference or growth performance of insect herbivores in transgenic silver birch (Betula pendula Roth)?

Transgenic silver birch (Betula pendula Roth) lines were produced in order to modify lignin biosynthesis. These lines carry COMT (caffeate/5-hydroxyferulate O-methyltransferase) gene from Populus tremuloides driven by constitutive promoter 35S CaMV (cauliflower mosaic virus) or UbB1 (ubiquitin promoter from sunflower). The decreased syringyl/guaiacyl (S/G) ratio was found in stem and leaf lignin of 35S CaMV-PtCOMT transgenic silver birch lines when compared to non-transformed control or UbB1-PtCOMT lines. In controlled feeding experiments the leaves of transgenic birch lines as well as controls were fed to insect herbivores common in boreal environment, i.e., larvae of Aethalura punctulata, Cleora cinctaria and Trichopteryx carpinata (Lepidoptera: Geometridae) as well as the adults of birch leaf-feeding beetles Agelastica alni (Coleoptera: Chrysomelidae) and Phyllobius spp. (Coleoptera: Curculionidae). The feeding preferences of these herbivores differed in some cases among the tested birch lines, but these differences could not be directly associated to lignin modification. They could as well be explained by other characteristics of leaves, either natural or caused by transgene site effects. Growth performance of lepidopteran larvae fed on transgenic or control leaves did not differ significantly.

Animals↗
PubMed2007

Differential expression of phenylpropanoid and related genes in brown-midrib bm1, bm2, bm3, and bm4 young near-isogenic maize plants.

The expression of phenylpropanoid and related genes was investigated in bm1, bm2, bm3, and bm4 near-isogenic maize plants at the 4-5 leaf stage using a gene-specific cell wall macro-array. The bm3 mutant, which is mutated in the caffeic acid O-methyltransferase (COMT) gene, exhibited the lowest number of differentially expressed genes. Although no other phenylpropanoid gene had an altered expression, two distinct OMT and two cytochrome P450 genes were overexpressed suggesting the activation of alternative hydroxylation/methylation pathways. The bm1 mutant had the highest number of differentially expressed genes, all of which were under-expressed. Bm1 mutant plants were affected not only in cinnamyl alcohol dehydrogenase (bm1 related CAD) gene expression as expected, but also in the expression of other CAD/SAD gene family members and several regulatory genes including MYB, ARGONAUTE and HDZip. As originally believed, the bm1 mutation could be localized at the CAD locus, but more probably in a gene that regulates the expression of the CAD gene family. The profile of under-expressed genes in the bm2 mutant is nearly similar to that of bm1. These genes fell under several functional categories including phenylpropanoid metabolism, transport and trafficking, transcription factors and regulatory genes. As the bm2 mutant exhibited a lower guaiacyl (G) unit lignin content, the bm2 mutation could affect a regulatory gene involved, perhaps indirectly, in the regulation, conjugation or transport of coniferaldehyde, or the establishment of G-rich maize tissues. The pattern of gene expression in bm4 plants, characterized by the over-expression of phenylpropanoid and methylation genes, suggests that the bm4 mutation likely also affects a gene involved in the regulation of lignification.

Biosynthetic Pathways↗
PubMed2006

A complete genetic association scan of the 22q11 deletion region and functional evidence reveal an association between DGCR2 and schizophrenia.

Several lines of evidence have established the presence of an association between a 3-Mb deletion in chromosome 22q11 and schizophrenia. In this paper we present a complete high-density SNP scan of this segment using DNA pools, and demonstrate significant association between two distinct regions and schizophrenia in an Ashkenazi Jewish population. One of these regions contains the previously identified COMT gene. The pattern of association and linkage disequilibrium (LD) in the second region suggest that DGCR2, which encodes a putative adhesion receptor protein, is the susceptibility gene. We confirmed the association between DGCR2 and schizophrenia through individual genotyping of 1,400 subjects. In a gene expression analysis the risk allele of a coding SNP associated with schizophrenia was found to be associated with a reduced expression of DGCR2. Interestingly, the expression of DGCR2 was also found to be elevated in the dorsolateral prefrontal cortex of schizophrenic patients relative to matched controls. This increase is likely to be explained by exposure to antipsychotic drugs. To test that hypothesis, we looked at rats exposed to antipsychotic medication and found significantly elevated levels of DGCR2 transcripts. The genetic and functional evidences here reported suggest a possible role of the DGCR2 gene in the pathology of schizophrenia and also in the therapeutic effects of antipsychotic drugs.

Alleles↗
PubMed2006

Molecular characterization of deletion breakpoints in adults with 22q11 deletion syndrome.

22q11 Deletion syndrome (22q11DS) is a common microdeletion syndrome with variable expression, including congenital and later onset conditions such as schizophrenia. Most studies indicate that expression does not appear to be related to length of the deletion but there is limited information on the endpoints of even the common deletion breakpoint regions in adults. We used a real-time quantitative PCR (qPCR) approach to fine map 22q11.2 deletions in 44 adults with 22q11DS, 22 with schizophrenia (SZ; 12 M, 10 F; mean age 35.7 SD 8.0 years) and 22 with no history of psychosis (NP; 8 M, 14 F; mean age 27.1 SD 8.6 years). QPCR data were consistent with clinical FISH results using the TUPLE1 or N25 probes. Two subjects (one SZ, one NP) negative for clinical FISH had atypical 22q11.2 deletions confirmed by FISH using the RP11-138C22 probe. Most (n = 34; 18 SZ, 16 NP) subjects shared a common 3 Mb hemizygous 22q11.2 deletion. However, eight subjects showed breakpoint variability: a more telomeric proximal breakpoint (n = 2), or more centromeric (n = 3) or more telomeric distal breakpoint (n = 3). One NP subject had a proximal nested 1.4 Mb deletion. COMT and TBX1 were deleted in all 44 subjects, and PRODH in 40 subjects (19 SZ, 21 NP). The results delineate proximal and distal breakpoint variants in 22q11DS. Neither deletion extent nor PRODH haploinsufficiency appeared to explain the clinical expression of schizophrenia in the present study. Further studies are needed to elucidate the molecular basis of schizophrenia and clinical heterogeneity in 22q11DS.

Adult↗
PubMed2003

L-DOPA biotransformation: correlations of dosage, erythrocyte catechol O-methyltransferase and platelet SULT1A3 activities with metabolic pathways in Parkinsonian patients.

The objectives of this study were to determine (1) the effects of dose and drug absorption on pathways of biotransformation of L-DOPA in Parkinsonian patients treated with Sinemet, and (2) the extent to which genetically-determined variations in the activities of erythrocyte catechol O-methyltransferase and/or platelet phenol sulfotransferase might be reflected in individual differences in L-DOPA metabolism. In the 19 patients studied, there were negative correlations between dosage or absorption and extent of O-methylation and of sulfation of L-DOPA or its metabolites. Levels of activity for erythrocyte COMT were also reflected in individual variation in the metabolism of L-DOPA. In contrast, differences in platelet phenol sulfotransferase were not reflected in differences in sulfation of L-DOPA or of its metabolites. If such a relationship did exist, it might have been obscured by the effects of high dosage of L-DOPA, effects which might have resulted from a deficiency of the sulfation cosubstrate 3'-phosphoadenosine 5'-phosphosulfate in patients taking higher doses of drug.

Adenosine Diphosphate↗
PubMed2003

Modifications of plasma and platelet levels of L-DOPA and its direct metabolites during treatment with tolcapone or entacapone in patients with Parkinson's disease.

We compared--retrospectively--the effects of a 3-month therapy with catechol- O-methyltransferase (COMT) inhibitors tolcapone (100 mg, t.i.d.) and entacapone (200 mg, t.i.d.), on L-DOPA metabolism in two groups of parkinsonian patients with motor fluctuations. Plasma and platelets concentrations of L-DOPA and its direct metabolites, dopamine and 3- O-methyldopa (3-OMD), were measured before starting treatment, after two weeks and at the end of treatment. Patients treated with tolcapone showed significant increases in plasma and platelet L-DOPA levels and marked reduction of plasma and platelet 3-OMD levels, both at short- and long-term. Entacapone did not modify L-DOPA levels, while inducing a less marked reduction of plasma and platelet 3-OMD concentrations, with respect to tolcapone, at both time points. Both drugs were similarly effective in increasing plasma and platelet levels of dopamine. These results confirm the different profiles of activity of the two drugs, with tolcapone proving more effective on both the intra- and extra-cellular levels of L-DOPA and 3-OMD.

Age Factors↗
PubMed2004

Entacapone improves the pharmacokinetic and therapeutic response of controlled release levodopa/carbidopa in Parkinson's patients.

The aim of this trial was to evaluate the effects of the COMT inhibitor entacapone on both the pharmacokinetic profile and clinical efficacy of controlled release levodopa in Parkinson's disease (PD) patients. Twelve PD patients experiencing "end-of-dose" type motor fluctuations were evaluated in this single-blind, randomized cross-over study. A single dose of either entacapone (200 mg) or placebo was co-administered with controlled release levodopa. Blood samples were taken every 30 minutes for 3 hours, and in 6 patients, sampling was continued for a further 3 hours. The clinical response to treatment was evaluated using the Unified Parkinson's Disease Rating Scale motor score. Addition of entacapone to levodopa treatment prolonged the "on" phase of the PD patients by 37% (p<0.05). This increased duration of 'on' time was concomitant with a significant increase in levodopa bioavailability (AUC). These data confirm the ability of entacapone to enhance the clinical efficacy of controlled release levodopa formulations, and provide further evidence that entacapone is of value in extending the benefits of levodopa in PD patients experiencing motor fluctuations.

Aged↗
PubMed2004

An open-label evaluation of the tolerability and safety of Stalevo (carbidopa, levodopa and entacapone) in Parkinson's disease patients experiencing wearing-off.

OBJECTIVES: To evaluate the tolerability, safety and efficacy of Stalevo (carbidopa, levodopa and entacapone) in Parkinson's disease (PD). BACKGROUND: Levodopa provides the most effective symptom control for the treatment of Parkinson's disease (PD). However, its long-term use is limited by the development of motor complications such as wearing-off. Catechol-O-methyltransferase (COMT) inhibitors such as entacapone extend the plasma half-life of levodopa and reduce 'off' time. Stalevo is a new levodopa product that combines carbidopa, levodopa and entacapone in one tablet. Clinical studies have not been reported with this compound. DESIGN METHODS: An open-label, multi-center US trial evaluated 169 consecutive PD patients experiencing end-of-dose wearing-off, with (n = 39) and without (n = 130) mild dyskinesia. Patients were switched from immediate-release carbidopa/levodopa to Stalevo and were treated for four weeks. Assessments included tolerability measures, adverse events profile, the disease-specific quality of life instrument PDQ-39, UPDRS parts II, III, and question 39 and investigator and patient global clinical assessments. RESULTS: 14 subjects (8%) discontinued treatment with Stalevo, of which 12 (7%) were due to adverse events. 11/130 (8.5%) subjects developed new onset dyskinesia and 17/39 (43.6%) of patients with existing dyskinesia reported a worsening in their dyskinesia. However, this was managed by a change in dose in 21.4% of patients and in another 10.7% dyskinesias resolved without any need for dose adjustment. Other side effects were infrequent and mild, the most common being nausea (12.4%) dizziness (6.5%) and somnolence (6.5%). Stalevo treatment resulted in significant improvements in PDQ-39 and UPDRS (II + III) scores (p < 0.001). Assessment of 'off' time demonstrated a reduction in off time in 32% of patients, compared with an increase in 7% of patients. Improvements were noted by both investigator (68.1%) and patient (68.6%) assessments. CONCLUSIONS: Switching PD patients experiencing wearing-off from carbidopa/levodopa therapy to Stalevo was safe, well tolerated and resulted in clinical improvement.

Adult↗
PubMed2006

Pharmacokinetic behaviour of levodopa and 3-O-methyldopa after repeat administration of levodopa/carbidopa with and without entacapone in patients with Parkinson's disease.

Addition of the catechol-O-methyltransferase (COMT) inhibitor entacapone (EN) prolongs plasma metabolism of levodopa (LD). Objectives were to determine the clinical response after EN addition and the plasma degradation of LD and 3-O-methyldopa [3-OMD]. Not optimum treated hospitalised patients with Parkinson's disease received the same LD dosage on the first day only with carbidopa (CD) and on the second day with CD and EN (t.i.d.) within a standardised setting. We scored motor symptoms and measured LD- and 3-OMD levels on both days at fixed moments. Motor impairment significant better improved probably due to significant higher maximum concentrations [C(max)] and computed area under the curve values of LD levels during the LD/CD/EN condition. Time to C(max) of LD was significantly delayed after the first two LD/CD/EN intakes. An impact of EN on 3-OMD levels appeared. A possibly augmented LD absorption and a prolonged LD metabolism after EN supplementation may contribute to a more continuous LD delivery to the brain.

Adult↗
PubMed2003

Allele frequencies of single nucleotide polymorphisms (SNPs) in 40 candidate genes for gene-environment studies on cancer: data from population-based Japanese random samples.

Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures. The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms (SNPs) of select genes, which may be included in future gene-environment studies on cancer in Japan. SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan. We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes: CYP1A1, CYP1B1, CYP2C9, CYP2C19, CYP2E1, CYP17A1, CYP19A1, AHR, ESR1, ESR2, ERRRG, PGR, EPHX1, EPHX2, HSD17B2, HSD17B3, GSTM2, GSTM3, GSTT2, GSTP1, NAT1, NAT2, COMT, ADH1A, ADH1B, ADH1C, ALDH2, NOS2A, NOS3, IL1A, IL1B, OGG1, NUDT1 [MTH1], DRD2, DRD3, DRD4, SLC6A4, NR3C1 [GCCR], MTHFR, and NQO1. In the present study, the Japanese allele frequencies were verified by using nationwide population samples.

Alleles↗
PubMed2005

Association of habitual smoking and drinking with single nucleotide polymorphism (SNP) in 40 candidate genes: data from random population-based Japanese samples.

Basic information on the association between lifestyle factors and candidate genes is valuable for genetic-environmental study. We screened the association of habitual smoking or drinking with polymorphism in 40 candidate genes for a total of 153 single nucleotide polymorphisms (SNPs) using a sample of 339 middle-aged, randomly selected Japanese men. Smoking and drinking statuses were elicited during questionnaire-based interviews. Genes were selected based on their possible involvement in genetic-environmental, life-style interactions and constitute the genes expressing xenobiotic metabolism enzymes, DNA repair enzymes, and other stress-related proteins. The P values of odds ratios to habitual smoking for CYP17A1, ESR1, EPHX1, GSTT2, ALDH2, NOS2A, OGG1, and SLC6A4 and those of odds ratios to habitual drinking for CYP1B1, ESR1, HSD17B3, GSTM3, COMT, ADH1C, ALDH2, NOS3, and NUDT1 were under 0.05. These variables were included in a stepwise logistic analysis in order to develop a predictive model for smoking or drinking behavior. In the final model, the only significant variables selected for smoking were OGG1, SLC6A4, EPHX1, ESR1, and CYP17A1, and for drinking, ALDH2 and NUDT1. The findings of the present study suggest that polymorphism in associated candidate genes plays a role in the habitual use of tobacco and alcohol among Japanese men.

Adult↗
PubMed2006

Tissue specificity of methylation and expression of human genes coding for neuropeptides and their receptors, and of a human endogenous retrovirus K family.

The purpose of the present study was to understand the tissue specificity of DNA methylation and the relationship between methylation and expression of genes with essential roles in neurodevelopment and brain function. We chose dopamine receptor genes (DRD1 and DRD2), NCAM, and COMT as examples of genes with CpG islands around the promoter region, and serotonin receptor genes (HTR2A and HTR3A), HCRT, and DRD3 as genes without CpG islands. Methylation states were investigated in fetal brain, fetal liver, placenta, and in adult peripheral leukocytes from three individuals by Southern blot and bisulfite-modified DNA sequencing. A repetitive sequence, human endogenous retrovirus (HERV)-K was also examined. All genes examined were almost completely unmethylated in brains. The genes with CpG islands were unmethylated regardless of their expression state. In contrast, genes without CpG islands showed various methylation patterns, which did not necessarily reflect the transcriptional activity of the genes. Most HERV-K loci were methylated, but some loci showed relatively low methylation in the placenta and liver. Interestingly, we found inter-individual differences in methylation levels in HTR2A and HCRT in the placenta and in some loci of HERV-K in the placenta and liver. The sample with the lowest methylation levels in the two unique genes showed higher methylation of HERV-K loci than the other samples. These results provide detailed information about the methylation states of the genes analyzed and evidence for inter-individual variations in methylation in both unique and repetitive sequences.

Brain↗
PubMed2004

Temporal administration of entacapone with slow release L-dopa: pharmacokinetic profile and clinical outcome.

Entacapone is a specific, peripherally acting catechol- O-methyltransferase (COMT) inhibitor that prevents peripheral degradation of L-dopa, thus improving its bioavailability. Entacapone is known to have pharmacokinetics similar to standard L-dopa but not to that of controlled-release (CR) L-dopa. The aim was to determine whether delayed entacapone administration may prolong CR L-dopa half-life in comparison to the co-administration modality. We compared plasma L-dopa concentrations after co-administration of CR L-dopa and entacapone or after administration of CR and a delayed (30 and 90 minutes) entacapone dose in 10 parkinsonian patients. The area under the concentration-time curve and other pharmacokinetic parameters were not changed by the delayed administration of entacapone. Different temporal modalities of entacapone administration had similar effects on CR L-dopa pharmacokinetics and on L-dopa-induced clinical improvement.

Aged↗
PubMed2003

Motor complications of Parkinson's disease.

Long-term treatment with levodopa in Parkinson's disease results in the development of motor complications, including drug failure, reduced duration of antiparkinsonian action (wearing off phenomenon), sudden shifts between under-treated and over-treated states (on-off phenomenon), freezing and involuntary movements such as levodopainduced dyskinesia. These motor complications can sometimes be solved with changes in the drug regimen, particularly the addition of dopamine agonists and catechol-O-methyltransferase (COMT) inhibitors and/or changes in levodopa dose, formulation and number of doses. Amantadine and selegiline can also be helpful in reducing motor fluctuations.

Drug Resistance↗
PubMed2006

The association between headache and Val158Met polymorphism in the catechol-O-methyltransferase gene: the HUNT Study.

The catechol-O-methyltransferase (COMT) gene contains a functional polymorphism, Val158Met, that has been found to influence human pain perception, and one study has found that migraine was less likely among those with the Val/Val polymorphism. In the 1995-97 Nord-Trøndelag Health (HUNT) Study, the association between the Val158Met polymorphism and headache was evaluated in a random sample of 2451 individuals. No association between Val158Met polymorphism and migraine was found. Among women, a lower prevalence of non-migrainous headache was found among individuals with the Val/Val genotype than among those with other genotypes (26.2% vs. 33.6%, p = 0.04). That non-migrainous headache was less likely among women with the Val/Val genotype may be an incidental finding, but should be investigated in further studies.

Adult↗
PubMed2006

Comparison of maize brown-midrib isogenic lines by cellular UV-microspectrophotometry and comparative transcript profiling.

The molecular mechanisms underlying cell wall digestibility in maize (Zea mays L.) have been studied in three sets of maize brown-midrib isogenic lines in the genetic background of inbreds 1332 (1332 and 1332 bm3), 5361 (5361 and 5361 bm3), and F2 (F2, F2 bm1, F2 bm2, and F2 bm3). Two complementary approaches, SSH (suppression subtractive hybridization) and microarray-based expression profiling, were used to isolate and identify candidate genes in isogenic lines for bm mutants. Metabolic pathway analysis revealed that transcriptional events caused by altering the expression of a single bm gene involve all metabolic and signaling pathways. 53 ESTs were differentially expressed in all three isogenic bm3 comparisons, whereas 32 ESTs were consistently differentially expressed in different bm isogenic lines in F2 background. About 70% ESTs isolated by SSH were not present on the unigene microarray, demonstrating the usefulness of the SSH procedure to identify genes related to cell wall digestibility. Together with lignin analysis by cellular UV-microspectrophotometry, expression profiling in isogenic bm lines proved to be useful to understand alterations at the sub-cellular and molecular level with respect to lignin composition. The down-regulation of COMT affected the expression of CCoAOMT genes and caused a reduced content both of G and S units in bm3 mutants.

Base Sequence↗
PubMed2004

The genes for schizophrenia: finally a breakthrough?

A number of susceptibility genes for schizophrenia have recently been identified. They have engendered excitement because replicate studies have attained greater consistency than in the past. In this review, we outline gene mapping methods, and briefly review their strengths and challenges. We also evaluate peer-reviewed genetic association studies that have implicated six selected genes: catechol-O-methyl transferase (COMT), neuregulin 1 (NRG1), dysbindin (DTNBP1), regulator of G-protein signaling 4 (RGS4), and G72 and D-amino-acid oxidase (DAAO). The available supporting evidence is variable. Though credible evidence is available for all of these genes, it is strongest for NRG1 and DTNBP1. Further studies, particularly exhaustive analyses of all polymorphisms at each locus, meta-analyses, and investigations of the likely function of risk alleles (variants) are desirable.

Carrier Proteins↗
PubMed1985

The effect of ring-fluorination on the rate of O-methylation of dihydroxyphenylalanine (DOPA) by catechol-O-methyltransferase: significance in the development of 18F-PETT scanning agents.

The three ring-fluorinated analogs of dihydroxyphenylalanine (DOPA) were synthesized and the kinetics of their O-methylation catalyzed by catechol-O-methyltransferase compared to those of DOPA. The affinities (Km) of 2-FDOPA, 5-FDOPA, DOPA, and 6-FDOPA were 20, 23, 55, and 552 microM, respectively, whilst the Vmax values were 4.0, 4.4, 5.0 and 5.4 nmol per min per mg protein. The importance of the low affinity and decreased rate constant of 6-FDOPA for COMT are discussed with regard to the use of 6-FDOPA as an 18-fluorine labeled probe for positron emission transaxial tomography (PETT).

Animals↗