ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Some 3–10% of Caucasians are deficient in CYP2D6 metabolism (poor metabolizers), due to inheritance of two defective alleles, whereas amplification of theCYP2D6gene results in ultrarapid metabolism in 1–2% of Caucasian populations. To examine the possible association betweenCYP2D6polymorphism and individual smoking behaviour, we analysed the prevalence ofCYP2D6genotypes among 292 long-term heavy smokers, 382 individuals with more variable smoking histories, and 302 never-smokers. The prevalence of ultrarapid metabolizers in heavy smokers (7.9%) was twofold compared to individuals with variable smoking habits (3.7%; odds ratio 2.3, 95% confidence interval 1.2–4.4), and fourfold compared with never-smokers (2.0%) (odds ratio 4.2, 95% confidence interval 1.8–9.8). The frequency of poor metabolizer genotype was approximately 2%, in each smoker group. However, when men and women were studied separately, the prevalence of poor metabolizer genotype was higher in male never-smokers (3.6%) than in variable smokers (2.7%) and heavy smokers (2.2%). Moreover, a trend test, adjusted by age, gender and cancer status, revealed a significant trend for the increased tobacco usage with increased metabolic capacity. Our results are in agreement with the assumption that increased CYP2D6 activity may contribute to the probability of being addicted to smoking.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The genotypic basis of interindividual variation in levels of induced CYP1A1 activity has been investigated by screening both theCYP1A1gene and theAhreceptor gene (AhR) for both previously described and novel polymorphisms. A 103-fold level of interindividual variation in induced CYP1A1 activity [ethoxyresorufinO-deethylase (EROD)] was observed in lymphocytes from a group of 30 Caucasian volunteers. High levels of induced EROD activity did not correlate with the presence ofCYP1A1*2orCYP1A1*4alleles or with theGSTM1null genotype. NovelCYP1A1alleles with the base substitutions C4151T, G-469A and C-459T respectively, were detected by screening the coding exons and approximately 1 kb of upstream sequence in 20 individuals by single-strand conformational polymorphism (SSCP) analysis but none of the three novel alleles appeared to be associated with high induced CYP1A1 activity in the study group. Screening of the 11 exons of theAhRgene by SSCP analysis confirmed the existence of the previously describedG1721Apolymorphism in a Caucasian population and a novel allele (G1768A which results in the amino acid substitution V5701) was also detected. The novel allele was very rare in Caucasians though more common in African-Americans. Individuals with at least one copy of the G1721AAhRvariant allele showed a significantly higher level of induced CYP1A1 activity compared with individuals negative for the polymorphism (P = 0.0001). A similar finding was obtained for induced CYP1A1 protein levels determined by immunoblotting. Levels of induced CYP1A1 activity were also found to show a sex difference with women showing a significantly lower induced activity compared with men. We conclude that genotypes for the G1721AAhRpolymorphism and gender appear to be determinants of levels of induced CYP1A1 activity and that interindividual variation in levels of induced CYP1A1 activity appears to be associated more with regulatory factors than polymorphism in theCYP1A1gene.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Cytochrome P450 1B1 (CYP1B1) participates in the metabolic activation of a number of procarcinogens including benzo[a]pyrene and the hydroxylation of 17β-estradiol at the C-4 position. In this study, we investigated the association betweenCYP1B1genetic polymorphism and breast or lung cancer incidence. TheAla-Serpolymorphism at codon 119 in presumed substrate recognition site 1 was significantly associated with the incidence of breast or squamous cell carcinoma of the lung. On the other hand,Leu-Valpolymorphism at codon 432 did not show any association to the cancers. An allele containing both Ala and Leu simultaneously, comprised 75% of alleles among 315 Japanese healthy controls, was significantly inversely associated with breast cancer incidence. When expressed in a recombinant system, thisCYP1B1cDNA showed the lowest 17β-estradiol 4-hydroxylase activity among four different variant forms of CYP1B1. Thus, inter-individual differences in activation of procarcinogens or metabolism of oestrogen originating from genetic polymorphisms of the humanCYP1B1gene may contribute to the susceptibility of human cancers.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Agranulocytosis is a rare, but serious adverse reaction to sulphasalazine. The polymorphic enzymeN-acetyltransferase 2 (NAT2) plays an important role in the metabolism of sulphasalazine. This study was conducted to analyse whether the risk of sulphasalazine-induced agranulocytosis is increased in slow acetylators. Patients were treated for inflammatory disease, mostly joint disease, with a mean dose of 2 g sulphasalazine daily. Thirty-nine patients reacted with agranulocytosis, while 75 patients had been treated for a minimum of 3 months without haematological side-effects. A population-based control panel of 448 individuals was used for comparison. All subjects were genotyped forNAT2by polymerase chain reaction followed by restriction enzyme digestion. The six most common allelic variants were analysed:NAT2*4,NAT2*5A,NAT2*5B,NAT2*5C,NAT2*6andNAT2*7. The proportion of slow acetylators was significantly higher in patients with sulphasalazine-induced agranulocytosis (69%) and population-based controls (64%) compared to patients who tolerated sulphasalazine (45%); odds ratio 2.71 [95% confidence interval (CI) 1.20; 6.15],P = 0.015, and odds ratio 2.17 (95% CI 1.32; 3.56),P = 0.002, respectively. Patients who developed agranulocytosis did not differ from population-based control subjects in the frequency of slow acetylators; odds ratio 1.25 (95% CI 0.62; 2.53),P = 0.535. The risk of agranulocytosis did not appear to be increased in slow acetylators, provided that the difference compared with sulphasalazine-treated control subjects was not due to a predominance of fast acetylators among patients with inflammatory joint disease. Instead, selection bias was suspected since more slow acetylators may have discontinued sulphasalazine therapy because of drug-intolerance.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Some patients with idiopathic Parkinson's disease experience hallucinations as a result of treatment with levodopa and dopamine agonists. There is evidence for some heterogeneity in these hallucinating patients based on duration of Parkinson's disease at onset of hallucinations. We compared the frequency of polymorphisms in the dopamine D2and D3receptor genes between patients with drug-induced hallucinations and non-hallucinating patients. Two polymorphisms close toDRD2and one inDRD3were studied. No association was found with the whole group of hallucinating patients and their controls. However, an association was found with late-onset hallucinations and theCallele of theTaqIA polymorphism, 10.5 kb 3′ toDRD2. This polymorphism may be in linkage disequilibrium with a mutation inDRD2or a nearby gene that predisposes to drug-induced hallucinations which occur later in the course of idiopathic Parkinson's disease.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Analysis of the expressed sequence tag (EST) database by sequence alignment allows a rapid screen for polymorphisms in proteins of physiological interest. The human zeta class glutathione transferaseGSTZ1has recently been characterized and analysis of expressed sequence tag clones suggested that this gene may be polymorphic. This report identifies threeGSTZ1alleles resulting from A to G transitions at nucleotides 94 and 124 of the coding region,GSTZ1*A – A94A124;GSTZ1*B – A94G124;GSTZ1*C – G94G124. Polymerase chain reaction/restriction fragment length polymorphism analysis of a control Caucasian population (n = 141) showed that all three alleles were present, with frequencies of 0.09, 0.28 and 0.63 forZ1*A,Z1*BandZ1*C, respectively. These nucleotide substitutions are non-synonymous, with A to G at positions 94 and 124 encoding Lys32to Glu and Arg42to Gly substitutions, respectively. The variant proteins were expressed inEscherichia colias 6X His-tagged proteins and purified by Ni-agarose column chromatography. Examination of the activities of recombinant proteins revealed that GSTZ1a–1a displayed differences in activity towards several substrates compared with GSTZ1b–1b and GSTZ1c–1c, including 3.6-fold higher activity towards dichloroacetate. This report demonstrates the discovery of a functional polymorphism by analysis of the EST database.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The O6-methylguanine-DNA methyltransferase (MGMT) is a critical defence against alkylation-induced mutagenesis and carcinogenesis. More than a 20-fold interindividual difference in the MGMT activity is known to exist among human cultured fibroblasts. We previously reported three allelic variants of the humanMGMTgene, namely V1, V2, and V3. Both V1 and V2 carry amino acid substitutions, Leu84Phe and Trp65Cys, respectively, while V3 has a silent mutation. In order to reveal the pharmacogenetic and ecogenetic significance of polymorphism in the humanMGMTgene, we investigated the in-vivo characteristics of V1 and V2 methyltransferase enzyme.Esherichia colistrain KT233 (ogt−,ada−) and mer−HeLa MR cells carrying a V1 sequence exhibited almost the same level of sensitivity againstN-methyl-N′-nitro-N-nitrosoguanidine (MNNG), as did those with a wild-type sequence. The level of methyltransferase protein in those cells was essentially the same as for the wild-type and V1 samples. On the other hand,E. coliand human cells expressing V2 cDNA showed a significantly reduced level of survival. In these cells, V2 protein was hardly detected, even though mRNA was produced normally. An in-vitro translation experiment revealed that the V2 sequence had the potential to produce methyltransferase protein, as did the wild-type and V1 sequences. There was also evidence for a small amount of V2 protein being produced but rapidly degraded, thus implying that the V2 molecule is unstablein vivo. Using purified recombinant proteins, we estimated the kinetic values of wild-type and variant form of enzymes, which would support these views. From these results, we concluded that the wild-type and V1 protein have similar enzymatic and physicochemical properties, while V2 protein is considered to be unstable and rare.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

A non-invasive urine analysis method to determine the in-vivo flavin-containing monooxygenase (FMO) activity catalysingN-oxidation of ranitidine (RA) was developed and used to phenotype a Korean population. FMO activity was assessed by the molar concentration ratio of RA and RANO in the bulked 8 h urine. This method was used to determine the FMO phenotypes of 210 Korean volunteers (173 men and 37 women, 110 nonsmokers and 100 smokers). Urinary RA/RANO ratio, representing the metabolic ratio and the reciprocal index of FMO activity, ranged from 5.67–27.20 (4.8-fold difference) and was not different between men and women (P = 0.76) or between smokers and nonsmokers (P = 0.50). The frequencies of RA/RANO ratios were distributed in a trimodal fashion. Among the 210 Korean subjects, 93 (44.3%) were fast metabolizers, 104 (49.5%) were intermediate metabolizers and 13 (6.2%) were slow metabolizers. Subsequently, the relationship between the ranitidineN-oxidation phenotypes andFMO3genotypes, determined by the presence of two previously identified mutant alleles (Glu158Lys: FMO3/Lys158and Glu308Gly: FMO3/Gly308alleles) commonly found in our Korean population was examined. The results showed that subjects who were homozygous and heterozygous for either one or both of the FMO3/Lys158and FMO3/Gly308mutant alleles had significantly lower in-vivo FMO activities than those with homozygous wild-type alleles (FMO3/Glu158and FMO3/Glu308) (P < 0.001, Mann–WhitneyU-test). Furthermore, the FMO activities of subjects with either FMO3/Lys158or FMO3/Gly308mutant alleles were almost identical to those having both FMO3 mutant alleles (FMO3/Lys158and FMO3/Gly308). These two mutant alleles located, respectively, at exons 4 and 7 in theFMO3gene appeared to be strongly linked bycis-configuration in Koreans. Therefore, we concluded that presence of FMO3/Lys158and FMO3/Gly308mutant alleles inFMO3gene is responsible for the low ranitidineN-oxidation (FMO3 activity) in our Korean population.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The frequency distributions of humanN-acetyltransferase 1 (NAT1*) alleles in various ethnic groups are largely unknown. This lack of information is in contrast to the many studies of ethnic differences inNAT2*alleles and phenotypes. Increasing interest in NAT1 due to its potential roles in carcinogen metabolism and cancer risk makes it desirable to know the distribution ofNAT1*alleles in various populations. Using a polymerase chain reaction-restriction fragment length polymorphism genotyping assay, the frequency ofNAT1*alleles in a Lebanese population was determined. Of 84NAT1*alleles assayed, 56% wereNAT1*4. AllelesNAT1*3,*10, and*14were found at frequencies of 0.036, 0.107, and 0.238, respectively. Five additional alleles (6%) differed from previously reported alleles. Nearly 50% of the population were heterozygous for aNAT1*14allele. The unusually high frequency ofNAT1*14alleles in Lebanese may be useful for epidemiological studies of the effects of the NAT1 polymorphism in this population.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID