摘要:

Impaired S-mephenytoin 4′-hydroxylation is a well-described genetic polymorphism affecting drug metabolism in humans. The reported population prevalence of the CYP2C19 poor metabolizer phenotype in Caucasians of European descent has been described as ranging from 0.9% to 7.7%. To address the question of whether the difference in the frequency of poor metabolizers represents an ethnic genetic microheterogeneity in the structure and expression of the CYP2C19 gene in Caucasian individuals, we performed a pooled analysis of available studies. Combined data from the 22 homogeneous studies showed that the frequency of poor metabolizers in healthy unrelated Caucasians determined by phenotyping was 2.8% (110 of 3990; 95% confidence interval 2.3–3.3). Data obtained from eight homogeneous studies that determined the frequency of poor metabolizers by genotyping showed that the genotypic frequency of poor metabolizers was 2.1% (28 of 1356; 95% confidence interval 1.3–2.8), consistent with the poor metabolizer frequency determined by phenotyping. In the extensive metabolizers, 26% (471 of 1786; 95% confidence interval 24.4–28.4) were heterozygotes. The observed frequencies of the three Mendelian genotypes were 73% forwt/wt, 26% forwt/m, and 2.1% form/m. Based on the overall phenotypic poor metabolizer frequency of 2.8%, the expected genotypic frequencies were 69% forwt/wt, 28% forwt/mand 2.8% form/m, which are in good agreement to the observed values. However, in the 84 Caucasian phenotyped and genotyped poor metabolizers, approximately 10% of the putative poor metabolizer alleles (17 of 168) were unknown. This study provides a systematic overview of the population distribution of the CYP2C19 poor metabolizer phenotype and CYP2C19 alleles and genotypes in healthy Caucasians living in different geographical areas, and shows a similar polymorphic pattern in the structure and expression of theCYP2C19gene in the worldwide Caucasian populations.

ISSN:0960-314X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Propafenone undergoes extensive metabolism both by phase I and phase II enzymes: cytochrome P4502D6 (CYP2D6) dependent polymorphic hydroxylation to its main metabolite 5-OH-propafenone, CYP3A4/1A2 dependentN-dealkylation and further glucuronidation and sulfation. Since CYP2D6 is not inducible by rifampicin, an important drug interaction between rifampicin and propafenone is not to be expected a priori. However, non-CYP2D6-dependent pathways may be induced as a case report described dramatically lowered plasma concentrations of propafenone with loss of dysrhythmia control associated with rifampicin treatment. Therefore, this study aimed to investigate induction properties of rifampicin on propafenone disposition in extensive metabolizers and poor metabolizers of CYP2D6. Six extensive metabolizers and six poor metabolizers ingested 600 mg rifampicin once daily for nine consecutive days. The day before the first rifampicin dose and on the day of the last rifampicin dose each individual received a single intravenous (IV) infusion of 140 mg unlabelled propafenone and 2 h later a single dose of 300 mg deuterated propafenone orally (PO). During enzyme induction maximum QRS prolongation decreased significantly after propafenone PO (21 ± 7% versus 13 ± 6% in extensive metabolizers,P< 0.01; 15 ± 6% versus 9 ± 6% in poor metabolizers,P< 0.01) and not after propafenone IV. In parallel, there were no substantial differences in pharmacokinetics of propafenone IV by rifampicin. However, bioavailability of propafenone dropped from 30 ± 15% to 10 ± 8% in extensive metabolizers (P< 0.01) and from 81 ± 6% to 48 ± 8% in poor metabolizers (P< 0.001). Following propafenone PO clearances throughN-dealkylation (4.1 ± 2.1 ml/min versus 23.5 ± 12.6 ml/min in extensive metabolizers,P< 0.01; 3.4 ± 1.3 ml/min versus 16.0 ± 5.5 ml/min in poor metabolizers,P< 0.001) and glucuronidation (123 ± 48 ml/min versus 457 ± 267 ml/min in extensive metabolizers,P< 0.05; 43 ± 9 ml/min versus 112 ± 34 ml/min in poor metabolizers,P< 0.01), but not 5-hydroxylation increased regardless of phenotype indicating substantial enzyme induction. Clearances to propafenone sulfate and conjugates of 5-OH-propafenone were significantly enhanced by rifampicin treatment in poor metabolizers (P< 0.01). Thus, induction of both phase I pathways (CYP3A4/1A2) and phase II pathways (glucuronidation. sulfation) of propafenone by rifampicin resulted in a clinically relevant metabolic drug interaction which was more pronounced in extensive metabolizers than in poor metabolizers with regard to percentage decrease in bioavailability of propafenone.

ISSN:0960-314X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The human dopamine D4receptor is a D2-like receptor which is a target for most common neuroleptics. Previous investigations have shown that this receptor displays a large polymorphic variation in the third intracellular loop involving a variable number of direct imperfect tandem repeats (VNTR) of 16 amino acids. The shortest and longest repeat variants reported to date contain two and 10 repeat units (D4.2and D4.10). No major pharmacological differences have been reported for the most common variants of this receptor (D4.2, D4.4and D4.7), although the D4.7was reported by us to display a slightly lower potency for dopamine in functional assays. Direct pharmacological and functional comparison of the longest and shortest variants in this study suggest no major discrepancies in pharmacological or functional profile between both receptors. Both receptors display, on average, a 15-fold and 90-fold lower potency for epinephrine and norepi-nephrine, respectively, compared with dopamine. We observed small increases in functional potency and affinity for dopamine and quinpirole at the D4.10receptor variant compared with the D4.2receptor. Our data indicate that there is no direct relationship between the length of the polymorphism and changes in pharmacology or functional activity. These findings are a suitable caution against the arbitrary pooling of D4receptor VNTR genotypes in genetic studies, based on length.

ISSN:0960-314X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The mouse cytosolic aldehyde dehydrogenase ALDH3A1 (encoded by theAldh3algene) has previously been shown in cell culture to be markedly inducible by 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD; dioxin), downregulated by the metabolism of functional CYP1A1/1A2 enzymes, and upregulated by a gene on Chr 7 that leads to endogenous oxidative stress. In order to study the regulation ofAldh3algene expression, we isolated two overlapping genomic sequences from a B6/CBA mouse genomic library that included the entireAldh3a1gene, along with considerable 5‘ and 3’ flanking sequences. TheAldh3a1gene was shown to span approximately 10 kb and comprise 11 exons including a noncoding first exon. The sequence of 3.18 kb upstream of exon 1 reveals numerous consensus transcription factor-binding sites, some of which were shown to be important in the positive and negative control ofAldh3algene expression; these include seven aromatic hydrocarbon response elements (AHREs), an electrophile response element (EPRE), and AP-1, C/EBPβ, c/EBPα, NF-KB, Sp1, and NF-1 putative binding sites. Deletion fusion constructs containing regions of theAldh3algene 5‘ flanking sequence, ligated to chloramphenicol acetyltransferase (CAT) or luciferase (LUC) reporter genes, were studied. Transient transfection experiments suggested that the 5’ flanking region of the gene contains a strong promoter, at least four functional AHREs appear to act cooperatively in causing dioxin-mediated upregulation, and a putative negative regulatory element (NRE) controls basal gene expression independent of dioxin inducibility. The dioxin-mediated upregulation ofAldh3alexpression in mouse hepatoma Hepa- 1c1c7 cell cultures was shown to depend exclusively on the aromatic hydrocarbon receptor.

ISSN:0960-314X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Cytochrome P450 (CYP) 2C19 is polymorphic with poor metabolizers representing 3–6% of Europeans and Africans, and 13–23% of Asians. Greater than 99% of the poor metabolizer alleles in Asian populations are defined by two single base pair mutations (CYP2C19*2andCYP2C19*3). We have recently reported an unprecedentedly high prevalence (71%) of CYP2C19-related poor metabolizer genotype individuals and poor metabolism of proguanil on two malarious islands of Vanuatu in eastern Melanesia. To elucidate this further, a total of 5538 individuals from 24 populations on 16 different islands of Vanuatu were genotyped. Of these, 61% had a poor metabolizer genotype (*2/*2,*2/*3 or*3/*3) with substantial variation among the populations (38–79%). The overall frequencies of CYP2C19*1 (wild-type),CYP2C19*2, andCYP2C19*3were 0,223, 0.633, and 0.144, respectively. A significant linear correlation was observed between heterozygosity and South latitude (r= 0.552,P< 0.05). The genotype frequencies of 21 of the 24 populations were consistent with Hardy-Weinberg expectations (P> 0.05). Comparisons of genetic, linguistic and geographical patterns among populations suggest that short range gene flow is largely responsible for the current distribution ofCYP2C19alleles in Vanuatu. Taken together with previous studies of nuclear genetic loci of Pacific island populations, these data predict that the poor metabolizer genotype is common throughout Polynesia and Micronesia and may be even more prevalent in western Melanesia than in Vanuatu. This suggests that the majority of Pacific Islanders metabolize a wide variety of clinically important drugs to a significantly lower degree than the average European.

ISSN:0960-314X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Variation at the UDP-glucuronosyltransferase (UGT) 1A1 gene promoter is present in humans. Variable numbers of TA repeats in the TATA box of this gene are found which are inversely related to levels of gene expression. We investigated this polymorphism in 658 individuals from a world-wide sample of 15 aboriginal and two admixed human populations. This study shows that there is a great deal of variability across ethnic groups with regard toUGT1A1allele frequencies, with the most common allele varying in frequency from 33% to 91%. Populations of African origin harbor four different alleles while non-African populations appear to have only two alleles. In addition, alleles associated with lower gene expression levels reach the highest frequencies in populations of African origin and lowest among Asians and Amerindians. Thus, more variability in the metabolism of drugs eliminated by UGT1A1 glucuronidation should be expected in populations of Sub-Saharan African origin. The sequence analysis of nine primate species shows that the number of TA repeats has increased during primate evolution achieving the largest number in humans. We suggest that the UGT1A1 promoter variability does not reflect historical relationships between populations and that it may be maintained by natural selection. Our findings are consistent with the proposal that the TA repeat variation is a balanced polymorphism.

ISSN:0960-314X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

We recently conducted a dose—response study of the effects of cocaine on several activity measures in the panel of BxD/Ty recombinant inbred mice. Animals were tested in an automated activity chamber over 2 days with i.p. saline on day 1 and i.p. cocaine on day 2, at one of four doses, 5, 15, 30 or 45 mg kg-1. The monitor recorded total distance traveled, nosepokes in a holeboard, repeated movements and time spent by an individual in proximity to the centre of the apparatus. Dose—response curves for locomotor activation, i.e. the difference between cocaine and saline scores, showed that for all strains tested, scores increased 5–30 mg kg-1. With few exceptions, locomotor activity at 45 mg kg-1was not significantly higher than that at 30 mg kg-1. Repeated movement scores showed patterns similar to locomotor activity and nosepokes tended to be progressively inhibited by increasing doses of cocaine. Recombinant inbred strain mean distributions for all behaviours and at all doses exhibited continuous, rather than discrete variation, thus providing evidence of multiple-gene effects on cocaine-related behaviours. Quantitative trait loci (QTL) analysis pointed to several chromosomal locations associated with variations in cocaine-related behaviours and some are either identical or close to QTL reported by others. In separate groups of animals, densities of dopamine D1, and D2receptors and dopamine uptake transporters were measured in the medial prefrontal cortex, caudate-putamen, nucleus accumbens and ventral midbrain. In all areas, all measures showed distributions consistent with polygenic influence and were associated with QTL. Of particular interest was our finding of a large segment on chromosome 15, which is related to dopamine receptor densities and cocaine-related behaviours.

ISSN:0960-314X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The ability to predict interindividual differences in drug efficacy or toxicity, based on genetic factors that influence drug disposition or drug action, is fast becoming a realistic goal. The purpose of the present study was to determine whether epibatidine, a prototypical nicotinic analgesic drug, exhibits pharmacogenetic variability in antinociceptive activity. Eight inbred mouse strains (A, AKR, BALB/c, C3H/He, C57BL/6, C57BL/10, DBA/2, andSM) were surveyed for their sensitivity to the antinociceptive effects of epibatidine. All strains exhibited statistically significant antinociception that peaked between 10 and 20 min following the systemic injection of 50μg/kg epibatidine. However, there was fourfold variability in the magnitude of peak effect between strains, withDBA/2, BALB/candAstrains showing much greater sensitivity than all others. A return to baseline nociceptive threshold at 30 min post-injection was observed for all but the A strain. In contrast, these mice exhibited significant antinociception for at least 3 h following epibatidine administration. Thus, expressing the data as area under the time-latency curve to take into account both the magnitude and duration of effect, epibatidine displayed approximately 20-fold higher antinociceptive potency in theAstrain compared with theC3H/Hestrain. The effects of epibatidine in both theAandC3H/Hestrains were dose-dependent and sensitive to antagonism by the selective neuronal nicotinic channel blocker mecamylamine. Taken together, these data demonstrate the existence of pharmacogenetic variability in neuronal nicotinic receptor-mediated antinociception between inbred stains of mice and presage the potential for similar variability in analgesic response to nicotinic-based analgesics among humans. Future studies will seek to identify the chromosomal loci underlying this variability.

ISSN:0960-314X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

TheN-acetyltransferase (NAT2) polymorphism has been suggested to be related to diabetic microvascular complications. To study the distribution ofNAT2genotypes in Caucasian type 1 diabetic patients with and without diabetic nephropathy, 214 adult type 1 diabetic patients and 53 healthy individuals were genotyped by polymerase chain reaction-restriction fragment length polymorphism. In addition, 75 young type 1 diabetic patients were genotyped, and 70 of them also phenotyped by caffeine. Of the adult patients, 83 had normal albumin excretion, 58 had micro-albuminuria, and 73 had overt diabetic nephropathy.NAT2allele frequencies were similarly distributed between the diabetic patients and healthy individuals: 0.29/0.25 (NAT2*4), 0.03/0.04 (NAT2*7B), 0.25/0.27 (NAT2*6A), and 0.43/0.44 (NAT2*5B), and within the diabetic subgroups. Because smoking is a known risk factor for diabetic nephropathy, nonsmoking and smoking patients were analysed separately.NAT2allele frequencies differed significantly between the nonsmoking normoalbuminuric, microalbuminuric and nephropathic patients: 0.18/0.41/0.30 (NAT2*4), 0.04/0.00/0.02 (NAT2*7B), 0.35/0.18/0.17 (NAT2*6A), 0.43/0.41/0.50 (NAT2*5B),P= 0.013. In nonsmoking fast acetylators odds ratio for microalbuminuria and nephropathy was 3.1 (95% confidence interval 1.36–7.05),P= 0.007 by logistic regression. In smokers, a nonsignificant odds ratio was found [0.31 (95% confidence interval 0.08–1.2),P= 0.09]. Smoking is a strong confounding factor in relation toNAT2analyses and diabetic nephropathy. According to our data, in nonsmoking type 1 diabetic patients fastNAT2genotype implies an increased risk for diabetic nephropathy.

ISSN:0960-314X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Androgens play an important role in the development of prostate cancer. Androgen regulating genes that show allelic variation may be susceptibility factors for the disease. One of these genes,CYP17, encodes the cytochrome P450c17α enzyme. It catalyses steroid 17α-hydroxylase/17,20 lyase activities at key points in testosterone biosynthesis. We investigated the association between a polymorphism in theCYP17gene and prostate cancer in a population-based case-control study. All individuals studied were Caucasians born in Sweden, 178 were consecutive clinical prostate cancer patients, and 160 were age-matched control individuals randomly selected from the same catchment area. DNA was extracted from blood samples. ACYP17gene fragment was amplified by polymerase chain reaction. TheMspAll restriction enzyme, which recognizes the base pair substitution, was used to identify the allelic variantsCYP17A1andCYP17A2.Significantly more men homozygous for theCYP17A1allele were found among prostate cancer patients compared with control individuals; odds ratio 1.61 (95% confidence interval 1.02; 2.53),P= 0.04. According to a preliminary report, theCYP17A1/A1genotype leads to higher circulating androgen levels, possibly by encoding for a more active androgen synthesizing CYP17 enzyme. Consequently, theCYP17A1/A1genotype, which was found in a higher frequency among prostate cancer patients, may prove to be one of the important susceptibility factors for prostate cancer. If verified, this genotype is likely to convey a larger risk on a population basis, than the rare hereditary prostate cancer genes do.

ISSN:0960-314X    

出版商:OVID    

年代:1999

数据来源: OVID