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At least 415 records · Page 23Linked to original sources
PubMed2005

Effects of the CYP3A5 genetic polymorphism on the pharmacokinetics of diltiazem.

BACKGROUND: The cytochrome P450 (CYP) 3A subfamily plays an important role in the metabolism of various endogenous and exogenous compounds. Among CYP3A subfamily members, CYP3A5 is polymorphically expressed and the CYP3A5*3 and CYP3A5*6 alleles are known not to express functional CYP3A5. Thus, these mutant alleles are thought to be responsible for interindividual variability of CYP3A activity. METHODS: Subjects possessing CYP3A5*1/*1, *1/*3 or *3/*3 received oral administration of diltiazem hydrochloride (60 mg), and plasma and urinary concentrations of diltiazem and its metabolite N-desmethyldiltiazem were measured. Before drug intake, cortisol metabolic clearance in each subject was measured to estimate in vivo CYP3A4 activity. RESULTS: The mean values of total oral diltiazem clearance of subjects with *1/*1, *1/*3 and *3/*3 were 183.4 +/- 39.4, 197.9 +/- 49.6 and 293.6 +/- 141.1 (l/h), respectively, and were not significantly different among the 3 genotype groups. The cortisol metabolic clearance was not significantly different among the three genotype groups, indicating that the CYP3A4 activity is not significantly different. CONCLUSION: The results suggest that CYP3A5*3 has only a minor effect on the pharmacokinetics and metabolism of diltiazem. Although our results did not indicate significance of CYP3A5, the effects of CYP3A5*3 on the metabolism of other CYP3A substrates remain to be investigated.

Adult↗
PubMed2006

Cellular isoform of the prion protein PrPc in human intestinal cell lines: genetic polymorphism at codon 129, mRNA quantification and protein detection in lipid rafts.

The cellular isoform of the normal prion protein PrP(c), encoded by the PRNP gene, is expressed in human intestinal epithelial cells where it may represent a potential target for infectious prions. We have sequenced the PRNP gene in Caco-2 and HT-29 parental and clonal cell lines, and found that these cells have a distinct polymorphism at codon 129. HT-29 cells are homozygous Met/Met, whereas Caco-2 cells are heterozygous Met/Val. The 129Val variant was also detected in Caco-2 mRNAs. Real-time PCR quantifications revealed that PrP(c) mRNAs were more expressed in HT-29 cells than in Caco-2 cells. These data were confirmed by studying the expression of PrP(c) in plasma membranes and lipid rafts prepared from these cells. Overall, these results may be important in view of using human intestinal cell lines Caco-2 and HT-29 as cellular in vitro models to study the initial steps of prion propagation after oral inoculation.

Caco-2 Cells↗
PubMed2005

Effect of itraconazole on the pharmacokinetics and pharmacodynamics of fexofenadine in relation to the MDR1 genetic polymorphism.

OBJECTIVE: Our objective was to evaluate the effect of itraconazole, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of fexofenadine, a P-glycoprotein substrate, in relation to the multidrug resistance 1 gene (MDR1) G2677T/C3435T haplotype. METHODS: A single oral dose of 180 mg fexofenadine was administered to 7 healthy subjects with the 2677GG/3435CC (G/C) haplotype and 7 with the 2677TT/3435TT (T/T) haplotype. One hour before the fexofenadine dose, either 200 mg itraconazole or placebo was administered to the subjects in a double-blinded, randomized, crossover manner with a 2-week washout period. Histamine-induced wheal and flare reactions were measured to assess the effects on the antihistamine response. RESULTS: In the placebo phase, pharmacokinetic parameters of fexofenadine showed no statistically significant difference between 2 MDR1 haplotypes; the area under the curve from time 0 to infinity (AUC(0-infinity)) of fexofenadine in the T/T and G/C groups was 5194.0 +/- 1910.8 and 4040.4 +/- 1832.2 ng.mL(-1).h(-1), respectively (P = .271), and the oral clearance (CL/F) was 530.9 +/- 191.1 and 806.0 +/- 355.3 mL.h(-1).kg(-1), respectively (P = .096). The disposition of itraconazole, a substrate of P-glycoprotein, was not significantly different between the 2 haplotypes. After itraconazole pretreatment, however, the differences in fexofenadine pharmacokinetics became statistically significant; the mean fexofenadine AUC(0-infinity) in the T/T group was significantly higher than that in the G/C group (15,630.6 +/- 5070.0 and 9252.9 +/- 2044.1 ng/mL.h, respectively; P = .007), and CL/F of the T/T subjects was lower than that of the G/C subjects (167.0 +/- 33.3 and 292.3 +/- 42.2 mL.h(-1).kg(-1), respectively; P < .001). Itraconazole pretreatment caused more than a 3-fold increase in the peak concentration of fexofenadine and the area under the curve to 6 hours compared with the placebo phase. This resulted in a significantly higher suppression of the histamine-induced wheal and flare reactions in the itraconazole pretreatment phase compared with those in the placebo phase. CONCLUSION: The effect of MDR1 G2677T/C3435T haplotypes on fexofenadine disposition are magnified in the presence of itraconazole. Itraconazole pretreatment significantly altered the disposition of fexofenadine and thus its peripheral antihistamine effects.

Adult↗
PubMed2006

Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action.

AIM: Our aim was to judge the importance of candidate pharmacogenetic modulators of the central nervous effects of levomethadone by both magnitude of the modulatory effect and frequency of the mutation to assess the utility of genotyping for clinical levomethadone therapy in a random sample of subjects that, by distribution of genotypes, resembled the clinical setting. METHODS: Candidate pharmacogenetic modulators were polymorphisms reported to be of functional consequence and therefore potentially important for metabolism, distribution, or pharmacodynamic action of levomethadone, consisting of genes coding for cytochrome P450 (CYP) 2B6 and 3A, as well as 1A2, 2C8, 2C9, 2C19, and 2D6, for P-glycoprotein (ABCB1), and for mu-opioid receptors (OPRM1). The central nervous effects of levomethadone were investigated by means of measuring pupil size in a random sample of 51 healthy volunteers for 9 hours after oral administration of 0.075 mg/kg levomethadone. Plasma concentrations of levomethadone and its metabolites were assessed concomitantly, and to judge the role of metabolites, the affinities of levomethadone and its metabolites at mu-opioid receptors were estimated by use of displacement of the selective mu-opioid receptor agonist [(3)H]-DAMGO ((3)H-[D-Ala(2),N-MePhe(4),Gly-ol(5)]-enkephalin). RESULTS: Pupil size decreased to -41.8% +/- 9.6% from baseline at 3.5 +/- 1.1 hours after levomethadone administration. Miosis was still manifest to a lower degree (-25.1% +/- 12.3%) at the end of the observation period. In carriers of the variant 118G allele (118A>G single-nucleotide polymorphism) of the mu-opioid receptor gene (OPRM1), levomethadone had a 1.74 times (95% confidence interval, 1.4-2.2 times) lower miotic potency (P < .001) as compared with noncarriers (concentration at half-maximum effects, 52.3 nmol/L; 95% confidence interval, 36.7-66.2 nmol/L). The maximum percent decrease in pupil diameter from baseline was 44.9% +/- 7.6%, 33% +/- 6.5%, and 24% +/- 6.9% for carriers of the OPRM1 118AA, AG, and GG genotypes, respectively (P < .001 for AG and GG versus wild type, without significant differences between AG and GG). Other candidate polymorphisms in the ABCB1 or in CYP genes had no significant influence on the effects of levomethadone, either because of lack of functional consequences or because of their low allelic frequency. The metabolites of levomethadone did not contribute to the effects as indicated by low metabolite plasma concentrations and their 120- to 1300-fold lower affinities at mu-opioid receptors as compared with levomethadone. CONCLUSIONS: Among polymorphisms in OPRM1, ABCB1, and CYP genes previously associated with functional consequences in a different context, the most important pharmacogenetic factor modulating the short-term effects of levomethadone is a polymorphism (OPRM1 118A>G) affecting mu-opioid receptors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

The thiopurine methyltransferase genetic polymorphism is associated with thioguanine-related veno-occlusive disease of the liver in children with acute lymphoblastic leukemia.

OBJECTIVE: Thiopurine metabolism was investigated in children with acute lymphoblastic leukemia treated in the United Kingdom Medical Research Council trial ALL97. This trial compared the efficacy and toxicity of thioguanine (INN, thioguanine) versus mercaptopurine. METHODS: Consecutive children were randomized to receive thioguanine or mercaptopurine during maintenance chemotherapy. Toxicity data were collected by an adverse event-reporting system with follow-up questionnaires. Red blood cell thiopurine methyltransferase (TPMT) activity and thioguanine nucleotide concentrations were measured by standard techniques. RESULTS: Of the children, 748 were randomized to thioguanine and 744 were randomized to mercaptopurine. There was no difference in the event-free survival rate between the 2 groups (80% and 81%, respectively, at 5 years). Thioguanine was associated with veno-occlusive disease (VOD) of the liver in 95 children, and persistent splenomegaly as a result of portal hypertension developed in 43 children. TPMT activity was significantly lower in the children in whom VOD developed, with a median of 13.4 U (range, 5.8-23 U) compared with 15.2 U (range, 5.3-27) in a control group of 161 leukemia patients in whom VOD did not develop (median difference, 1.8 U; 95% confidence interval, 0.9-2.7 U; P = .0001). TPMT activity in children with persistent splenomegaly was also lower than that in control subjects (median difference, 1.6 U; 95% confidence interval, 0.3-2.8 U; P = .012). There was no difference in red blood cell thioguanine nucleotide concentrations. CONCLUSIONS: Thioguanine was associated with liver damage in 11% of children randomized to thioguanine without an improvement in event-free survival rate. The association of lower TPMT activity with thioguanine-related liver damage could provide a means of identifying at-risk patients.

Adolescent↗
PubMed2005

Glutathione S-transferase M1 and T1 genetic polymorphisms are not related to the risk of hepatocellular carcinoma: a study in the Spanish population.

Glutathione S-transferases constitute a superfamily of enzymes that catalyse the inactivating conjugation of endogenous and environmental substrates involved in the pathogenesis of hepatocellular carcinoma (HCC) and glutathione. Genes encoding either glutathione S-transferase Mu-1 or Theta-1 (GSTM1 and GSTT1, respectively) isoforms are polymorphic. Homozygotes for the mutated inactive alleles of each gene are devoid of any specific enzymatic activity (null genotypes). Our aim was to investigate whether individuals with null GST genotypes have a higher risk of developing HCC. A total of 184 Caucasian Spanish patients with a diagnosis of HCC and 329 healthy controls of the same ethnic origin were included. Polymorphisms in GSTM1 and GSTT1 genes were identified through multiplex polymerase chain reactions, and the dihydrofolate reductase (DHFR) gene was used as internal control. No differences were found between the frequencies of GSTM1 (47.8% versus 45.3%) and GSTT1 (28.8% versus 23.1%) null genotypes in cases and controls, respectively, nor in the proportion of carriers of two, one or no active genotypes. Gender, age at diagnosis, tobacco use, chronic infection with hepatitis B or C virus and alcohol abuse did not influence these results. In conclusion, polymorphisms in GSTM1 and GSTT1 genes are not related to the incidence of HCC in a high-risk Spanish population.

Aged↗
PubMed2005

Association of genetic polymorphism of glutathione S-transferase M1, T1, P1 and susceptibility to bladder cancer.

OBJECTIVE: Glutathione-S-transferases (GSTs) are active in the detoxification of wide variety of endogenous or exogenous carcinogens. We examined the association of the GST gene polymorphism with sporadic bladder cancer patients in Northern India. MATERIAL AND METHODS: The study constituted of 106 bladder cancer cases and 370 age-matched controls. The GSTT1 and GSTM1 null genotypes were identified by multiplex PCR and GSTP1313 A/G by Polymerase Chain Reaction/Restriction Fragment Length Polymorphism method (PCR/RFLP). RESULTS: We observed non-significant association in null alleles of the GSTM1 (p = 0.611, OR = 1.12, 95% CI = 0.72-1.74 and GSTT1 (p = 0.135, OR = 1.45, 95% CI = 0.89-2.37) with risk of bladder cancer. However, the G/G genotype of the GSTP1 gene polymorphism was highly significant when compared to controls (p=0.000, OR = 7.12, 95% CI = 3.14-16.16). The combined analysis of the three risk genotypes demonstrated further increase in the risk of bladder cancer (p = 0.000, OR = 7.29 95% CI = 2.81-18.93). CONCLUSION: Our study demonstrated that GSTP1313 G/G polymorphism is a strong predisposing risk factor for bladder cancer. Combination of three GST genotypes association exhibiting gene-gene interaction further substantiates the increased risk of bladder cancer.

Carcinoma, Transitional Cell↗
PubMedDate not supplied

GSTP1, GSTM1, and GSTT1 genetic polymorphisms in patients with cryptogenic liver cirrhosis.

We investigated glutathione S-transferase (GST) P1 Ile (105) Val, T1, and M1 polymorphisms in 45 patients with documented cryptogenic cirrhosis and 56 healthy control subjects. Polymerase chain reaction-based procedures were performed in the studied populations to confirm the genotypes of GSTT1, M1, and P1. Ile/Val and Val/Val GSTP1 genotypes were more frequent in the patients with cirrhosis (n=39, 87%) than in the control subjects (n=10; 18%) (odds ratio [OR] 34.04; 95% confidence interval [CI] 10.70 to 108.31, P<0.001). Among these patients with cirrhosis, 16 were heterozygous and 23 were homozygous, whereas only one person in the control group was homozygous. The GSTM1 null genotype was also more prevalent in cirrhotic patients than in healthy control subjects (OR 6.83, 95% CI 2.53 to 18.42, P<0.001). The rate of GSTT1 deletion did not show a significant difference between the two groups (OR 2.35, 95% CI 0.76 to 7.28, P=0.111). To our knowledge, this is the first evidence that GSTP1 and GSTM1 polymorphisms may be related to the development of cirrhosis by unknown mechanisms. The significant association of cryptogenic cirrhosis with Val/Val GSTP1 genotype encoding a low detoxification activity protein implicates this polymorphism as a risk factor for the occurrence of the disease.

Acyltransferases↗
PubMed2004

[Polycystic ovary syndrome in pubertal period: clinical, biological, metabolic and genetic polymorphism].

Polycystic ovary syndrome (PCOS) is a common cause of hyperandrogenism in adolescent girls. In its complete post menarchal expression, the syndrome is characterized by the association of typical clinical, biological, and ultrasonographic findings. Many factors have contributed to our knowledge of different clinical forms of PCOS in adolescent girls. They are helpful for clarifying misleading situations in a period of life when diagnosis of PCOS implies a treatment for many years and may interfere with gynecological outcome. During the last 3 years, we had the opportunity to manage in our unit 45 adolescent girls with ovarian hyperandrogenism: 32 of them had PCOS and the other 13 functional ovarian hyperandrogenism defined by clinical and biological hyperandrogenism without ultrasonographic abnormality. In this review, we report, from our personal experience as well as from recent literature data, the different clinical expressions of PCOS in the pubertal period: the classical post menarchal form, the exceptional pre menarchal form, the post precocious pubarche and the post precocious puberty forms, the familial expression as well as the dominant metabolic expression.

Adolescent↗
PubMed2006

DNA damage repair and genetic polymorphisms: assessment of individual sensitivity and repair capacity.

PURPOSE: To study the repair capacity after X-ray irradiation in human peripheral blood cells of healthy subjects, in relation to their genotypes. METHODS AND MATERIALS: The peripheral blood of 50 healthy subjects was irradiated in vitro with 2 Gy of X rays and the induced DNA damage was measured by Comet assay immediately after irradiation. DNA repair was detected by analyzing the cells at defined time intervals after the exposure. Furthermore, all subjects were genotyped for XRCC1, OGG1, and XPC genes. RESULTS: After X-ray irradiation, persons bearing XRCC1 homozygous variant (codon 399) genotype exhibited significantly lower Tail DNA values than those bearing wild-type and heterozygous genotypes. These results are also confirmed at 30 and 60 min after irradiation. Furthermore, XPC heterozygous subjects (variant codon 939) showed lower residual DNA damage 60 min after irradiation compared with wild-type and homozygous genotypes. CONCLUSION: The results of the present study show that polymorphisms in DNA repair genes could influence individual DNA repair capacity.

Adult↗
PubMed2004

Genetic polymorphisms associated with thrombophilia and vascular disease in women with unexplained late intrauterine fetal death: a multicenter study.

OBJECTIVE: We determined whether gene polymorphisms associated with thrombophilia and vascular disease as etiologic factors were involved in the pathogenesis of pregnancy-associated complications. METHODS: We conducted a multicenter case-control study in which we studied 94 women with late unexplained intrauterine fetal death (IUFD) and 94 healthy women with at least one uncomplicated full-term pregnancy and no history of IUFD. We obtained blood samples from all subjects and analyzed their DNA for 12 common polymorphisms of thrombophilic and vascular genes (factor V Leiden, factor V H1299R, prothrombin G20210A, factor XIII V34L, MTHFR C677T, MTHFR A1298C, beta-fibrinogen-455 G to A, PAI-1 4G/5G, GPIIIa L33P, HFE C282Y, apolipoprotein B R3500Q, and apolipoprotein E2/E3/E4). RESULTS: We found no significant association between any of the polymorphisms investigated and IUFD. Subgroup analyses involving various combinations of polymorphisms and in which gestational age and fetal weight were corrected for also showed no significant results. CONCLUSIONS: Our data represent the largest study to date with respect to thrombophilic and vascular gene polymorphisms in IUFD. In accordance with others, we challenge the importance of thrombophilic and vascular gene polymorphisms in the pathogenesis of this condition.

Adult↗
PubMed2006

Hormonal imbalance in two types of endometrial cancer and genetic polymorphism of steroidogenic enzymes.

OBJECTIVES: Modern data on endometrial cancer (EC) incidence demonstrate that it is one of the most prevalent gynecologic malignancies. It is possible that some allelic polymorphisms of the genes involved in steroidogenesis or steroid metabolism differently contribute into susceptibility to described types of this disease, namely to type I (which is considered to be hormone dependent) and type II. METHODS: Distribution of allelic polymorphisms of CYP17 (17alpha-hydroxylase/17,20-lyase), CYP19 (aromatase), catechol-O-methyltransferase (COMT) and CYP1B1 (primarily, estrogen 4-hydroxylase) genes was compared totally in 156 endometrial cancer patients, approximately two-third of who belonged (on the basis of case history and some characteristics of host and tumor) to type I of the disease, and one-third to type II. Blood leukocytes were used as source of normal DNA for PCR-genotyping. RESULTS: No differences were found in distribution of CYP17 and CYP1B1 genotypes between patients belonging to type I or II of the disease. On the other side, in case of CYP19, the ratio of incidence of A6A6 genotype to the frequency of A1A6 and A3A6 genotypes was higher in type II patients (1.0) than in type I patients (0.3). Besides, incidence of high activity (HH) COMT genotype was higher among patients with type I of disease than in patients with type II of it (33.3% versus 14.7%, OR=2.9, z=1.96, p=0.05) revealing tendency to the lower inactivation of catecholestrogens in the latter group. CONCLUSION: It may be suggested that more aggressive clinically and frequently receptor-negative type II of endometrial cancer is associated with indirect signs of mainly intratumoral hyperproduction of estrogens (excess of CYP19 A6A6 genotype) without their sufficient inactivation into methoxyderivatives that warrants further study.

Adult↗
PubMed2004

Chemiluminescent detection of genetic polymorphisms based on mismatch hybridization: application to cytochrome P4501A1.

An assay that makes use of differences in thermal stability between perfectly and imperfectly matched hybrids in combination with a sensitive chemiluminescence detection system was developed and applied to the identification of CYP1A1 polymorphisms. In this assay, two oligonucleotide probes for each polymorphic site were designed: one perfectly matching the wild type allele, the other perfectly matching the mutant allele. The genotypes were determined by calculating the ratio of signals obtained from the two probes. The method described here allows for the rapid, simple and cost-effective detection of DNA polymorphisms. Compared with fluorescence- and microarray-based assays, this method provides an alternative for genotyping where costly equipment or specialized reagents are not available.

Base Pair Mismatch↗
PubMed2005

The associations of p53 overexpression with p53 codon 72 genetic polymorphism in esophageal cancer.

Variations in p53 codon 72 have been identified as significant predisposing factors for various cancers, but molecular mechanisms remain unclear. We investigated associations of p53 overexpression with codon 72 variants and other factors with esophageal cancer. Status of p53 overexpression was determined by immunohistochemical staining. Codon 72 polymorphisms and mutation of p53 was identified by PCR-RFLP and direct sequencing from exons 4 to 9, respectively. We evaluated 126 patients who underwent esophagectomy in the National Taiwan University Hospital, and found that the status of p53 overexpression was significantly influenced by presence of codon 72 polymorphisms. After adjustment for other possible confounders, the incidence of p53 overexpression was significantly decreased in patients with Pro/Pro genotype with an odds ratio (OR) of 0.21 (95% CI: 0.067-0.64) (p = 0.0065) compared with incidence in patients with Arg/Arg genotype. The incidence of p53 overexpression was additively increased with environmental exposure to cigarette smoke, alcohol, and areca quid. When compared with individuals exposed to only one of these environmental risk factors, patients who had exposure to two or three risk factors had ORs of 6.11 (95% CI: 1.80-20.75) and 6.22 (95% CI: 1.81-21.34) for p53 overexpression, respectively. Elderly patients (age >70 years) were also more likely to have p53 overexpression, with an OR of 5.63 (95% CI: 1.53-20.64) compared with overexpression among patients aged less than 55 years. Forty-one patients received further evaluation of p53 mutation. There was also a higher incidence of, but without reaching a statistical significance, p53 mutation in patients with p53 overexpression (OR[95% CI]: 2.18 [0.52-9.6]) and codon 72 Arg/Arg genotype (OR [95% CI] of 0.8 [0.13-4.2], comparing genotypes of Pro/Pro and Arg/Pro with Arg/Arg). Our data provide the first observations that the presence of p53 codon 72 variants can be a significant factor influencing p53 overexpression in esophageal cancer, with overexpression also influenced by combined or prolonged environmental exposures.

Aged↗