摘要:

ObjectiveMutations in theABCB1gene have been associated with decreased expression and net function of P-glycoprotein (P-gp). We investigated the modulation of the central nervous effects of loperamide resulting fromABCB1genetic variants.MethodsOn two occasions, 20 healthy volunteers received 24 mg loperamide suspension orally and, in a double-blind randomized two-way crossover fashion, 800 mg quinidine or placebo orally 1 h before loperamide. Pupil size was measured for 5 h following loperamide administration, and plasma concentrations of loperamide and quinidine were measured for 6 h. Single nucleotide polymorphisms and haplotypes including G2677T(A) (exon 21) and C3435T (exon 26) were analysed for their relation to plasma concentrations of quinidine and loperamide and to the miotic effects of loperamide.ResultsLoperamide plasma concentrations with quinidine co-administration were about twice as high as those without quinidine. TheABCB1haplotype G2677/T3435 was associated with the highest loperamide plasma concentrations, which were about 1.5 times higher than in non-carriers of this haplotype. Plasma concentrations of quinidine did not differ among carriers and non-carriers of genetic variants. When quinidine was co-administered with loperamide, pupil size decreased. Without quinidine it changed only minimally. TheABCB1TT3435 genotype was associated with the most pronounced increase of the miotic effects of loperamide when quinidine was co-administered. This was accompanied by a tendency toward higher plasma loperamide in TT3435 carriers.ConclusionsOur data support a functional importance of theABCB1mutations for plasma concentrations and central nervous actions of the opioid loperamide.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectiveRenal dysfunction is a common and costly adverse outcome of long-term treatment with calcineurin inhibitors (CNIs). We conducted a retrospective, case–control study to test whether the risk of renal dysfunction in liver transplantation patients receiving CNIs is associated with the 2677G>T transversion in exon-21 of the gene (ABCB1) encoding P-glycoprotein. A total of 120 non-Hispanic white patients were evaluated.ResultsThe overall incidence of renal dysfunction by year 3 post-transplantation was 40%. The frequency of renal dysfunction was reduced among patients with anABCB12677TT genotype, as compared to those with a 2677GG genotype. Subjects with a heterozygote genotype behaved phenotypically like the 2677GG group. Comparing those subjects with a 2677TT genotype to the combined group of subjects with a 2677GG, TG, AT, or AG genotype resulted in an odds ratio of 0.26 (0.09–0.77). When subjects were stratified by gender, the frequency of renal dysfunction was reduced among men with anABCB12677TT genotype, relative to men with different genotypes. A similar odds ratio was obtained for women, but it did not achieve significance. When 18 subjects with an elevated SCr concentration just prior to surgery were excluded from the year 3 analysis, the association between the 2677TT genotype and chronic renal dysfunction in the remaining cohort was strengthened comparing genotype groups.ConclusionsBased on these results, we conclude that homozygosity for theABCB12677T (S893) allele is associated with reduced risk of chronic renal dysfunction among liver transplantation patients receiving an immunosuppressive regimen containing CNIs.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Advances in transplantation technology have brought about great benefits to patients suffering from organ failure, but the problem still remains of complications induced by steroids used for post-transplant immunosuppression. Among the side-effects caused by steroids, non-traumatic osteonecrosis of the femoral head (ONF) constitutes a serious problem. The same protocol for steroid administration induces ONF in some patients, but not in others, indicating the presence of individual difference in steroid sensitivity. We hypothesized that this difference might be mediated by the drug-transport protein, P-glycoprotein (P-gp), and investigated the relationship between single nucleotide polymorphisms in the multidrug resistance gene 1 (ABCB1,MDR1) encoding P-gp and ONF. Subjects comprised 136 patients receiving kidney transplantation. Thirty patients developed post-transplant ONF. Genomic DNA was extracted from peripheral blood, and genotypes ofABCB1C3435T (exon 26) and G2677T/A (exon 21) were determined by direct sequencing. Multivariate analyses based on clinical information were performed to determine the relationship betweenABCB1genotypes and ONF. The dose/concentration (D/C) ratios of tacrolimus were also determined to estimate the activity of P-gp in patients with different genotypes ofABCB1C3435T (CC, CT, TT), and in those who did and did not develop ONF. TheABCB13435TT genotype showed a significantly lower incidence of ONF (adjusted odds ratio = 0.10,P= 0.034). The D/C ratio in the 3435TT genotype was significantly higher than that in the 3435CC genotype. The D/C ratio in patients developing ONF was significantly higher than in those patients who did not develop ONF. The results suggest increased activity of P-gp in patients with the 3435TT genotype and in those who did not develop ONF. TheABCB12677 homozygous variant type also showed a lower incidence of ONF (adjusted odds ratio = 0.26,P= 0.056). The 3435T and 3435C alleles were in linkage disequilibrium with the 2677T and the 2677G alleles, respectively, in the study population. An assessment of C3435T and G2677T/A polymorphisms preceding steroid treatment could be useful for predicting the resistance to ONF development.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectiveWe previously reported that a T−786←C polymorphism in the 5′−flanking region of the endothelial nitric oxide synthase gene and smoking were independently associated with coronary spasm; however, the interaction between this polymorphism and smoking remains to be elucidated.MethodsWe analyzed 209 men and 238 women who were admitted consecutively at our institution; all subjects received an intracoronary injection of acetylcholine (ACh) while undergoing coronary angiography for evaluation of chest pain: all subjects had no significant coronary stenosis. We divided these subjects into four groups: non-smokers with T/T genotype (Control Group A); non-smokers with C/T or C/C genotype (Group B); smokers with T/T genotype (Group C); and smokers with C/T or C/C genotype (Group D). We further examined quantitative coronary angiographies of the left anterior descending coronary artery in a subset of 54 consecutive men and 53 consecutive women.ResultsThe frequencies of coronary spasm in Group B (male: 61%, female: 78%), Group C (62%, 59%) and Group D (91%, 92%) were significantly higher than in Group A (30%, 38%). In the males, ACh-induced vasoconstriction was greatest in Group D, and the change was weakest in Group A. In the females, ACh-induced vasoconstrictions were significantly greater in Groups B, C and D than in Group A. The T−786←<<?toc>Cpolymorphismandsmokingcombinetoincreasetheriskofcoronaryspasm.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

One of seven poor metabolizers of coumarin found in Thai subjects was previously genotyped as heterozygote for theCYP2A6*4(whole deletion) andCYP2A6*9. Thus, we aimed to investigate the relationship between the genetic polymorphism in the TATA box of theCYP2A6gene (CYP2A6*9), expression levels of CYP2A6 mRNA and coumarin 7-hydroxylase activities in human livers. Levels of CYP2A6 mRNA were quantified by real-time quantitative reverse transcriptase-polymerase chain reaction. The mean expression levels of CYP2A6 mRNA in individuals withCYP2A6*1/*4,CYP2A6*1/*9andCYP2A6*4/*9were 58%, 71% and 21% of the individuals genotyped asCYP2A6*1/*1, respectively. The mean in-vitro coumarin 7-hydroxylase activities in subjects carryingCYP2A6*1/*4,CYP2A6*1/*9andCYP2A6*4/*9were 41%, 71% and 12%, respectively, compared to those of the subjects judged as wild-type.Vmaxvalues for coumarin 7-hydroxylation in the liver microsomes from human subjects with genotypes ofCYP2A6*1/*1,CYP2A6*1/*4,CYP2A6*1/*9andCYP2A6*4/*9were 0.58, 0.26, 0.44 and 0.13 nmol/min/nmol total P450, respectively. CYP2A6 protein levels in human liver microsomes with theCYP2A6*4and theCYP2A6*9alleles were markedly decreased. These results suggest that the genetic polymorphism in the promoter region of theCYP2A6gene (CYP2A6*9) reduced the expression levels of CYP2A6 mRNA and protein in human livers, resulting in the decrease of coumarin 7-hydroxylase activities. Individuals judged asCYP2A6*4/*9were expected to be poor metabolizers, having extremely low activity of CYP2A6.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The cytochrome P450 (CYP) isozyme CYP2C19 metabolizes clinically important drugs, including the anti-malarial proguanil currently used for multi-drug resistantPlasmodium falciparummalaria. CYP2C19 activity varies among geographical regions due to high frequencies of two null alleles (CYP2C19*2/*3) in Asian and especially Pacific populations. Previously, we reported an unprecedentedly high frequency of CYP2C19 poor metabolizers (PM) within populations of Vanuatu, which suggested even higher PM frequencies in Papua New Guinea. We examined CYP2C19 allele frequencies of three malarious populations from inland East Sepik Province, Papua New Guinea to evaluate this prediction and the use of proguanil in malaria treatment programs. These Papua New Guinean populations have PM frequencies intermediate between island South-east Asia and Vanuatu, most likely resulting from genetic drift during the settlement of the Pacific. This study highlights the medical consequences of population origins and the need for a better understanding of the genetic diversity of our global species.

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:2003

数据来源: OVID