ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The objective of this investigation was to screen for potential endogenous substrates for CYP2D6. Using recombinant CYP2D6, together with hepatic microsomes fromCYP2D6-transgenic mice, human liver microsomes, and a specific anti-CYP2D6 monoclonal antibody, it was ascertained that CYP2D6 does not significantly metabolize the endogenous phenylethylamines 2-phenylethylamine, octopamine, synephrine, 3-methoxy-p-tyramine, 4-methoxy-m-tyramine, metanephrine, and normetanephrine, nor the indolethylamines tryptamine, serotonin, 6-methoxytryptamine, and melatonin, nor the β-carbolines harman, norharman and tryptoline. However, the indolethylamines 5-methoxy-N,N-dimethyltryptamine (5-MDMT) and pinoline (6-methoxy-1,2,3,4-tetrahydro-β-carboline) showed relatively high affinity for CYP2D6 in a spectral binding assay (Ks28±5, and 0.5±0.3 μm (mean±SEM), respectively) and wereO-demethylated only by CYP2D6 in a panel of 15 recombinant common human P450s. Pinoline and 5-MDMTO-demethylase activities were 35- and 11-fold greater in liver microsomes fromCYP2D6-humanized mice, respectively, than those in liver microsomes from control mice. Moreover, the increased activities were completely inhibited by an anti-CYP2D6 monoclonal antibody. Kinetic analysis with recombinant CYP2D6 gaveKmandkcatvalues for 5-MDMT and pinolineO-demethylations of 12±1 μm and 65±1 min−1and 1.8±0.3 μm and 26±1 min−1, respectively. These two substrates can be added to 5-methoxytryptamine, which we have recently reported to be an endogenous CYP2D6 substrate. CYP2D6 is therefore a relatively highly specific, high-affinity, high-capacity 5-methoxyindolethylamineO-demethylase. Polymorphic cytochrome CYP2D6 may therefore exert an influence on mood and behavior by theO-demethylation of these 5-methoxyindolethylamines found in the brain and pineal gland. These processes may also impact on mental and neurological health. The findings may open new vistas for the determination of CYP2D6 phenotype.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectiveCYP2E1 bioactivates environmental protoxins and metabolizes alcohol. CYP2E1 is induced by alcohol and cigarette smoking and may contribute to metabolic tolerance in alcoholics. TheCYP2E1*1Dpolymorphism has been associated with greater CYP2E1 inducibility. One objective was to determine the frequency of the variant allele in eight ethnic groups. Further, the Canadian Native Indian, South-east Asian Canadian and Caucasian Canadian groups were stratified by alcohol and nicotine dependence (as measured by DSM-IV criteria) to examine the potential association ofCYP2E1*1Dwith drug dependence.Results and conclusionsWe found a significantly greater frequency of theCYP2E1*1Dallele among Indo-Asian Canadians (0.31), Chinese Canadians (0.19), Taiwanese (0.20), Japanese Canadians (0.18), African Americans (0.13), African Canadians (0.10) and Canadian Native Indians (0.09) compared to Caucasian Canadians (0.02). Although the power of the association study was low among some subgroups, theCYP2E1*1Dgenotype (subjects with at least one variant allele) was associated with alcohol as well as nicotine dependence. Specifically, Canadian Native Indians dependent on nicotine alone or alcohol alone exhibited significantly greaterCYP2E1*1Dfrequencies compared to non-drug dependent controls, while the variant frequency among Southeast Asians dependent on nicotine was greater than their non-drug dependent counterparts. We also found thatCYP2E1*1Dgenotype was associated with significantly greater 3-hydroxycotinine per cigarette in African Americans. The variable frequency ofCYP2E1*1Damong ethnic groups suggests a greater risk for diseases putatively related to CYP2E1 in some non-Caucasian ethnic groups. The association ofCYP2E1*1Dwith alcohol and nicotine dependence suggests that CYP2E1 may contribute to the development of these dependencies.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Individual differences in the psychomotor stimulant effects of cocaine are influenced by genetic factors. Several quantitative trait loci (QTL) have been identified for cocaine-induced locomotor activation using the AXB/BXA recombinant inbred series of strains derived from the A/J (A) and C57BL/6J (B6). The aim of the present study was to conduct an independent analysis of cocaine-induced activation in the AcB/BcA recombinant congenic strains. The AcB/BcA RC series consists of 37 inbred strains derived from reciprocal backcrosses between the A and B6, followed by systematic inbreeding. Locomotor activity was measured in a computerized open-field apparatus following intraperitoneal administration of saline and cocaine (20 mg/kg). Linkage maps constructed with 625 informative microsatellite markers were used to identify chromosomal regions associated with cocaine difference scores. Significant (P<0.00001) regions were identified on chromosomes 1 (13–25.7 and 36.9–58.5 cM), 5 (1–28 and 84–86 cM), 6 (7–26.35 cM), 7 (9.4–27.8 cM), 9 (9–28 cM), 13 (21–37 cM), 16 (36–66 cM), 17 (22.5–24.5 cM) and 18 (45–48 cM). Multiple regression analysis demonstrated that a subset of four markers, including D5Mit182 (24 cM), D5Mit409 (84 cM), D7Mit83 (26.5 cM) and D13Mit54 (35 cM), accounted for 90% of the genetic variance in cocaine difference scores. The results of the present study provide confirmation for a number of QTL on chromosomes 1, 5, 6, 9, 16 and 17 which were previously identified in the recombinant inbred AXB/BXA and BXD strains that share a common B6 ancestor.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectiveThe aryl hydrocarbon receptor repressor (AhRR) protein may dimerize with the AhR nuclear translocator (ARNT) and may compete with the aryl hydrocarbon receptor (AhR) to bind the xenobiotic responsive elements. The result is a negative feedback mechanism that involves a down regulation of all genes regulated by the AhR transcription factor which positively regulates the expression of theCytochrome P-4501A1gene (CYP1A1).MethodsThe structure of theAhRRgene was reconstituted, then the genetic polymorphisms of this gene including the promoter were investigated and the link between these polymorphisms, CYP1A1 inducibility and lung cancer incidence in a French population was examined. Four polymorphisms were found, two in the coding region (609G>C and 1977G>C) and two in the 5′-untranslated region (−96G>A and−869A>T). Among the four polymorphisms, only one, the 609G>C has been previously described. The 609G>C and 1977G>C are localized respectively in exon 6 and 12 and lead to Pro554Ala and Asp641His substitutions, respectively. To evaluate the frequency of these allelic variants, a DNA library of a case–control study of lung cancer (164 controls and 171 patients) was screened. These polymorphisms were detected at the same allele frequency (0.40 for 609C, 0.05 for 1977C, 0.24 for−96A and 0.17 for−869T) in both controls and patients. Statistical analysis did not show any relationship between all the mutations found and CYP1A1 inducibility and lung cancer incidence.ConclusionNone of the polymorphisms were found to play a key role in CYP1A1 inducibility or in the susceptibility to develop lung cancer.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

BackgroundCytochrome P450 2E1 (CYP2E1) and NAD(P)H:quinone oxidoreductase (NQO1) catalyze the activation of some environmental procarcinogens present in tobacco smoke (i.e. nitrosoamines and heterocyclic amines). We conducted a hospital based case–control study to evaluate the potential association between genetic polymorphisms ofCYP2E1(C1019T in the 5′flanking region) andNQO1(C609T in exon 6) and bladder cancer risk in Asian population.MethodsThe study population was comprised of 218 histologically confirmed prevalent bladder cancer cases and 199 controls without cancer or systemic illness. PCR–restriction fragment length polymorphism based methods were used for the genotyping analyses and unconditional logistic regression model for the statistical evaluations.ResultsThe risk of bladder cancer increased with the amount of smoking (Pfor trend<0.01). The frequency ofCYP2E1c1/c1 genotype was significantly higher in bladder cancer patients (57.9%) than in the controls (47.9%) (OR = 1.8, 95% CI = 1.1–2.9). Similarly, theNQO1C/C genotypes were significantly more prevalent in the patients (45.8%) than in the controls (37.6%) (OR = 1.6, 95% CI = 1.0–2.7). The risk for bladder cancer increased with the number of the putative risk genotypes (Pfor trend = 0.03); the most remarkable risk was observed for heavy smokers with bothCYP2E1c1/c1 andNQO1C/C genotypes (OR = 13.8, 95% CI = 3.9–48.6) when compared to non/light smokers with other genotypes.ConclusionOur findings suggest thatCYP2E1andNQO1genotypes may play an important role in development of smoking related bladder cancer among Korean men.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

BackgroundParaoxonase (PON1), a HDL-associated enzyme, protects against toxicity from specific organophosphorus compounds and oxidized lipids. Common polymorphisms in thePON1gene have been identified and characterized in the coding region, 5′ regulatory region and 3′ UTR. The Q192R coding region polymorphism determines substrate-dependent differences in catalytic efficiency of hydrolysis. The −108CTpolymorphism in the 5′ regulatory region has a significant effect onPON1expression, with the −108Callele expressing on average twice the level of plasma PON1 as the −108Tallele. In addition to the effects of regulatory and coding region polymorphisms on PON1 levels and activity, plasma PON1 levels are also developmentally regulated. Since PON1 levels are important in determining resistance to specific organophosphorus compounds, the time course of appearance of PON1 in newborns is of great interest.ResultsWe report here that PON1 levels plateau between 6 to 15 months of age, and that variability in the age at which PON1 levels plateau is quite variable among individuals. In mice and rats, plasma PON1 activity reaches a plateau at 3 weeks of age. In mice that lack endogenous PON1, human transgenes encoding eitherPON1Q192orPON1R192under the control of the humanPON1regulatory sequences exhibited a similar time course of expression as that seen in wild-type mice, indicating conservation of the developmental regulatory elements between mouse and humanPON1.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Cholecystokinin modulates the release of dopamine and dopamine-related behaviours in the mesolimbic pathway, where cholecystokinin and dopamine coexist in dopaminergic neurones. Because cholecystokinin and its receptors (A and B) have a functional interaction with dopaminergic neurotransmission, alterations in them may constitute a predisposition for Parkinson's disease. We performed a case–control study to investigate the association between the cholecystokinin system and Parkinson's disease using genetic markers for three genes: cholecystokinin and its two receptors (A and B). One hundred and sixty patients with Parkinson's disease and 160 controls, matched for age, gender, ethnic origin and area of residence, were recruited. Cholecystokinin−45C>T, cholecystokinin-A receptor 779T>C and cholecystokinin-B receptor 1550G>A gene polymorphisms were studied using polymerase chain reaction-restriction fragment length polymorphism analyses. These three gene polymorphisms showed no correlation with risk of Parkinson's disease; however, the cholecystokininCT/TTgenotype was associated with a 4.429-fold increased risk for visual hallucinations in Parkinson's disease. Cholecystokinin-A receptor and B receptor polymorphisms, considered alone, showed no correlation with hallucinations in Parkinson's disease; however, a combined effect was found in patients with hallucinations harboring both the cholecystokininCT/TTand cholecystokinin-A receptorTC/CCgenotypes. Parkinson's disease patients harboring this genotype have a 5.922-fold increased risk for developing visual hallucinations. These results suggest that, in Chinese, visual hallucinations in Parkinson's disease are associated with cholecystokinin−45C>T polymorphism, and this association was still observed in the presence of the cholecystokinin-A receptorTC/CCgenotype, indicating a possible interaction of these two genes in the visual hallucinogenesis in Parkinson's disease.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The polymorphism of thiopurine methyltransferase (TPMT) was studied in 306 healthy Brazilians who were classed, on the basis of self-declared colour and ancestry, as Euro-derived (n= 81), Afro-derived (n= 18) or having interethnic admixture (n= 204). TPMT activity (range 0.17–25.93 U) displayed a trimodal distribution of high (>11.3 U; 9% of individuals), intermediate (5–11.3 U; 9.8%) and low (0.17 U; 0.3%) phenotypes. The occurrence of the TPMT mutations 238G>C, 460G>A and 719A>G was investigated in all individuals with low or intermediate phenotype, and in 43 with high-activity phenotype. None and two mutant alleles were associated with high- or low-activity phenotypes, respectively, whereas one mutant allele was detected in 26 of the 30 intermediate phenotype individuals. The allele frequencies ofTPMT*2,TPMT*3AandTPMT*3Cdid not differ between individuals classed as Euro-derived (0.76%, 2.03% and 2.54%, respectively) or having interethnic admixture (0.60%, 1.81% and 1.81%, respectively). Furthermore, within each of these groups, the frequencies ofTPMT*3AandTPMT*3Cwere not significantly different.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID