There exists a marked inter-individual variability of P-glycoprotein expression and activity, which can be of clinical importance due to the large number of drugs that are substrates for the transporter. Previously identified polymorphisms in the MDR1 gene belong to important factors causing this phenomenon. Our aim was to investigate the frequency of major functional SNPs of the MDR1 gene coding for P-glycoprotein in the Czech population. DNA was isolated from whole blood of 189 healthy, young and unrelated subjects (99 females and 90 males, aged from 23 to 28 years). The genotypes of polymorphic positions C3435T, G2677T/A, C1236T and T-76A were determined by PCR-RFLP. Observed allelic frequencies were 56.5%, 46.0%, 0.53%, 44.5% and 37.6% for the alleles 3435T, 2677T, 2677A, 1236T and -76A, respectively. We have found 64 subjects homozygous for 3435T, 42 for 2677T, 40 for 1236T and 31 for -76A alleles. The allelic distribution complies well with Hardy-Weinberg equilibrium. Allelic frequencies of functionally important MDR1 variants are in the Czech population similar to that of other Caucasian populations.

• MeSH
• dospělí MeSH
• frekvence genu MeSH
• lidé MeSH
• P-glykoprotein genetika   MeSH
• polymorfismus genetický * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• P-glykoprotein MeSH

BACKGROUND: P-glycoprotein (P-gp/MDR1), a member of the ATP-binding cassette (ABC) transporters super family, encoded by the ABCB1/MDR1 gene, is one of suggested respiratory tract protection components, found in various tissues with a barrier function, such as tracheobronchial epithelium and lung parenchyma. As an ATP-dependent pump, P-gp extrudes lipophilic particles out of cells and acts as a gatekeeper against numerous xenobiotics, with a protective role in mediating DNA damage, secretion of toxic compounds, apoptosis and the immune response. Therefore, a presence of MDR1 polymorphisms and altered P-gp expression may be important for pathogenesis of reduced lung inflammatory response on cigarette smoke exposure, as well as for the severity of chronic obstructive pulmonary disease and lung cancer pathogenesis and treatment efficacy. METHODS AND RESULTS: We have analyzed data available from experimental and clinical studies performed to establish the role of MDR1 polymorphisms, especially the 3435C>T variation, and P-gp expression in pathogenesis and clinical outcome of human respiratory diseases. CONCLUSIONS: Although there are indications that altered expression of P-gp and/or polymorphisms of MDR1 gene play an important role in respiratory diseases pathogenesis and treatment, their exact role and relevance are insufficiently investigated, with exception of certain chemotherapeutic agents' efficacy in lung cancer treatment. Further research in this field, including bigger series of patients, is necessary for better understanding of respiratory diseases' pathogenesis and treatment.

• Klíčová slova
• COPD, MDR1 polymorphisms, P-gp expression, lung cancer, respiratory diseases,
• MeSH
• DNA genetika   MeSH
• genetická predispozice k nemoci * MeSH
• lidé MeSH
• nemoci dýchací soustavy genetika   metabolismus   MeSH
• P-glykoprotein biosyntéza   genetika   MeSH
• P-glykoproteiny genetika   metabolismus   MeSH
• polymorfismus genetický * MeSH
• regulace genové exprese * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• ABCB1 protein, human MeSH Prohlížeč
• DNA MeSH
• P-glykoprotein MeSH
• P-glykoproteiny MeSH

OBJECTIVES: The aim of prospective study was to evaluate the therapeutic efficacy of piritramide in patients after removal of parathyroid glands in relation to MDR1 genotype. In the treatment of moderate acute postoperative pain, piritramide plays a major role. It is difficult to predict its optimal therapeutic efficacy and tolerability in individual patients. METHODS: We compared the effect of piritramide in 56 patients after surgical removal of parathyroid glands in a prospective study. We evaluated pain intensity, pain difference and sum of pain difference (SPID) using visual analogue scale (VAS in mm) and adverse effects in the relationship with the MDR1 - polymorphism of G2677T/A. RESULTS: In the wild-type group (2677GG), there was maximal pain difference of 30.6 ± 24.9 and SPID of 209.33 ± 95.80 while in genotype 2677TT and 2677GT, the corresponding values were 19.5 ± 25.5 and 147.07 ± 91.38, respectively. In group of patients with wild type of 2677GG genotype, there was 80 % of responders with more than 50 % reduction in VAS as compared to baseline while in group with carriers of 2677T allele, there are only 39 % of responders present (χ² = 5. 83; p = 0.016). Furthermore, the total consumption of piritramide was lower in comparison with the variant-allele carrying group (p = 0.008). The total incidence of adverse drug reactions was observed in 40 % of patients with wild type of 2677GG genotype when compared to 83% in the group carrying the variant allele (χ² = 7.92; p = 0.005). Significantly more patients in the wild-type group were satisfied with postoperative pain treatment in comparison to the variant allele group (χ² = 6. 49; p = 0.0109). CONCLUSION: We observed a better analgesic effect of piritramide and a decreased incidence of side effects in the wild-type genotype (2677GG) group, when compared with variant-allele carrying patients (Tab. 2, Fig. 1, Ref. 7).

• MeSH
• lidé středního věku MeSH
• lidé MeSH
• měření bolesti * MeSH
• opioidní analgetika terapeutické užití   MeSH
• P-glykoprotein genetika   MeSH
• paratyreoidektomie MeSH
• pirinitramid terapeutické užití   MeSH
• polymorfismus genetický * MeSH
• pooperační bolest farmakoterapie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• opioidní analgetika MeSH
• P-glykoprotein MeSH
• pirinitramid MeSH

OBJECTIVES: The aim of our study was to evaluate impact of CYP2D6 and MDR1 polymorphisms on the analgesic efficacy of tramadol in patients after a knee arthroscopy. BACKGROUND: Pharmacokinetics of tramadol and its metabolites is stereoselective and displays high interindividual variability correlating with polymorphic CYP2D6 in the population. Available data provide controversial results regarding the analgesic efficacy of tramadol in subjects with different CYP2D6 genotypes. METHODS: Pain intensity was assessed using visual analogue scale at 2 and 24 hours after the knee arthroscopy in 156 patients. Polymorphisms CYP2D6*3,*4,*5,*6, and gene duplication and C3435T in MDR1 gene were analyzed by PCR - RFLP. RESULTS: Mean VAS2h value in the whole study group was 44.0 ± 16.5 mm. Mean pain difference, was lowest in the UM group and highest in the PM group. The pain difference varied significantly among the CYP2D6 subgroups (F = 4.29; p = 0.006) with significant differences between homEM vs hetEM, homEM vs PM, and UM vs PM subgroups. There were no significant differences among MDR1 subgroups with regards of pain difference. Mean tramadol consumption was 2.47 ± 1.17 mg/kg during the 24 h period. There were no significant differences in the drug consumption, reporting of adverse reactions, need for rescue analgesic medication or verbal description of pain among the CYP2D6 or MDR1 genotype subgroups. CONCLUSION: CYP2D6 plays a significant role in tramadol analgesic efficacy. The non-opioid analgesia in PMs was associated with better subjective pain relief in patients after a knee arthroscopy (Tab. 3, Ref. 18).

• MeSH
• artroskopie MeSH
• cytochrom P-450 CYP2D6 genetika   MeSH
• dospělí MeSH
• frekvence genu MeSH
• heterozygot MeSH
• kolenní kloub chirurgie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• měření bolesti MeSH
• opioidní analgetika terapeutické užití   MeSH
• P-glykoprotein genetika   MeSH
• polymorfismus genetický * MeSH
• pooperační bolest farmakoterapie   MeSH
• tramadol terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytochrom P-450 CYP2D6 MeSH
• opioidní analgetika MeSH
• P-glykoprotein MeSH
• tramadol MeSH

Paroxetine-induced sexual dysfunction represents a frequent treatment complication of otherwise efficient antidepressants. The genetic polymorphism of pharmacokinetic genes may contribute to the occurrence of such dysfunctions. This study presents the effect of MDR1 gene polymorphisms on sexual function in 18 women with bulimia nervosa, 18 women with anxiety disorders, and 19 healthy control subjects. It also deals with the relation between MDR1 gene polymorphisms and paroxetine-induced sexual dysfunction. The results demonstrated that MDR1 G2677T/A gene polymorphism allele carriers treated with paroxetine presented with difficulties with orgasm (p = .008) and lubrication (p < .001).

• MeSH
• antidepresiva druhé generace aplikace a dávkování   MeSH
• bulimia nervosa farmakoterapie   genetika   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mutace genetika   MeSH
• P-glykoprotein genetika   MeSH
• P-glykoproteiny MeSH
• polymorfismus genetický * MeSH
• sexuální dysfunkce psychické chemicky indukované   genetika   MeSH
• studie případů a kontrol MeSH
• úzkostné poruchy farmakoterapie   genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABCB1 protein, human MeSH Prohlížeč
• antidepresiva druhé generace MeSH
• P-glykoprotein MeSH
• P-glykoproteiny MeSH

ATP Binding Cassette B1 (ABCB1) is a transporter with a broad substrate specificity involved in the elimination of several carcinogens from the gut. Several polymorphic variants within the ABCB1 gene have been reported as modulators of ABCB1-mediated transport. We investigated the impact of ABCB1 genetic variants on colorectal cancer (CRC) risk. A hybrid tagging/functional approach was performed to select 28 single nucleotide polymorphisms (SNPs) that were genotyped in 1,321 Czech subjects, 699 CRC cases and 622 controls. In addition, six potentially functional SNPs were genotyped in 3,662 German subjects, 1,809 cases and 1,853 controls from the DACHS study. We found that three functional SNPs (rs1202168, rs1045642 and rs868755) were associated with CRC risk in the German population. Carriers of the rs1202168_T and rs868755_T alleles had an increased risk for CRC (P(trend) = 0.016 and 0.029, respectively), while individuals bearing the rs1045642_C allele showed a decreased risk of CRC (P(trend) = 0.022). We sought to replicate the most significant results in an independent case-control study of 3,803 subjects, 2,169 cases and 1,634 controls carried out in the North of Germany. None of the SNPs tested were significantly associated with CRC risk in the replication study. In conclusion, in this study of about 8,800 individuals we show that ABCB1 gene polymorphisms play at best a minor role in the susceptibility to CRC.

• MeSH
• alely MeSH
• dospělí MeSH
• genetická predispozice k nemoci * MeSH
• genotyp MeSH
• kolorektální nádory diagnóza   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• modely genetické MeSH
• P-glykoprotein genetika   MeSH
• P-glykoproteiny MeSH
• polymorfismus genetický * MeSH
• riziko MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• ABCB1 protein, human MeSH Prohlížeč
• P-glykoprotein MeSH
• P-glykoproteiny MeSH

AIM: Cutaneous T-cell lymphoma (CTCL) is a group of T-cell malignancies that develop in the skin. Though studied intensively, the etiology and pathogenesis of CTCL remain elusive. This study evaluated the survival of CTCL patients in the 1st Department of Dermatovenereology of St. Anne's University Hospital Brno. It included analysis of 19 polymorphic gene variants based on their expected involvement in CTCL severity. MATERIAL AND METHODS: 75 patients with CTCL, evaluated and treated at the 1st Department of Dermatovenereology of St. Anne´s University Hospital Brno, Faculty of Medicine, Masaryk University, were recruited for the study over the last 28 years (44 men and 31 women, average age 58 years, range 20-82 years). All patients were genotyped for 19 chosen gene polymorphisms by the conventional PCR method with restriction analysis. A multivariate Cox regression model was calculated to reveal genetic polymorphisms and other risk factors for survival. RESULTS: The model identified MDR Ex21 2677 (rs2032582) as a significant genetic factor influencing the survival of the patients, with the T-allele playing a protective role. A multivariate stepwise Cox regression model confirmed the following as significant independent risk factors for overall survival: increased age at admission, clinical staging of the tumor, and male sex. CONCLUSION: We showed that the TT genotype at position 2677 of the MDR1 gene exhibited statistically significant longer survival in CTCL patients. As such, the TT genotype of MDR1 confers a significant advantage for the CTCL patients who respond to treatment.

• Klíčová slova
• CTCL, mycosis fungoides, polymorphism-MDR1, skin T-cell lymphoma,
• MeSH
• dospělí MeSH
• genotyp MeSH
• kožní T-buněčný lymfom * genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádory kůže * genetika   patologie   MeSH
• polymorfismus genetický MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

ATP-binding cassette (ABC) drug efflux transporters limit intracellular concentration of their substrates by pumping them out of cell through an active, energy dependent mechanism. Several of these proteins have been originally associated with the phenomenon of multidrug resistance; however, later on, they have also been shown to control body disposition of their substrates. P-glycoprotein (Pgp) is the first detected and the best characterized of ABC drug efflux transporters. Apart from tumor cells, its constitutive expression has been reported in a variety of other tissues, such as the intestine, brain, liver, placenta, kidney, and others. Being located on the apical site of the plasma membrane, Pgp can remove a variety of structurally unrelated compounds, including clinically relevant drugs, their metabolites, and conjugates from cells. Driven by energy from ATP, it affects many pharmacokinetic events such as intestinal absorption, brain penetration, transplacental passage, and hepatobiliary excretion of drugs and their metabolites. It is widely believed that Pgp, together with other ABC drug efflux transporters, plays a crucial role in the host detoxication and protection against xenobiotic substances. On the other hand, the presence of these transporters in normal tissues may prevent pharmacotherapeutic agents from reaching their site of action, thus limiting their therapeutic potential. This chapter focuses on P-glycoprotein, its expression, localization, and function in nontumor tissues and the pharmacological consequences hereof.

• MeSH
• biologický transport fyziologie   MeSH
• ledviny metabolismus   MeSH
• lidé MeSH
• mozek metabolismus   MeSH
• P-glykoprotein genetika   metabolismus   MeSH
• placenta metabolismus   MeSH
• polymorfismus genetický MeSH
• těhotenství MeSH
• tenké střevo metabolismus   MeSH
• testis cytologie   metabolismus   MeSH
• tkáňová distribuce MeSH
• xenobiotika metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• P-glykoprotein MeSH
• xenobiotika MeSH

Detailed understanding of the mechanisms employed in transfer of drugs across the placenta is essential for optimization of pharmacotherapy during pregnancy. Disclosure of drug efflux transporters as an "active component" of the placental barrier has brought new important insights into the field of transplacental pharmacokinetics. P-glycoprotein (P-gp, MDR1) is the first discovered and so far the best characterized of drug efflux transporters, whose role in the regulation of drug disposition to the fetus has been extensively studied. Expression of P-gp in the placental trophoblast layer was confirmed at the mRNA and protein levels in all phases of pregnancy, and several in vitro and in vivo studies demonstrated functional activity of the transporter in materno-fetal drug transport. P-gp is able to actively pump drugs and other xenobiotics from trophoblast cells back to the maternal circulation, providing thus protection to the fetus. This review summarizes the current knowledge on the expression, localization and function of P-gp in the placenta. In addition, we include the latest data concerning transcriptional regulation of placental P-gp expression and polymorphisms of the MDR1 gene. Clinical significance of placental P-gp and its future perspectives for pharmacotherapy during pregnancy are also discussed.

• MeSH
• geny MDR MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• maternofetální výměna látek MeSH
• messenger RNA metabolismus   MeSH
• P-glykoprotein genetika   metabolismus   MeSH
• placenta cytologie   metabolismus   MeSH
• těhotenství MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• messenger RNA MeSH
• P-glykoprotein MeSH

BACKGROUND: The ABCB1 gene encodes P-glycoprotein implicated in the development of cellular drug resistance. The aim of this study was to develop high-resolution melting (HRM) analysis for determination of ABCB1 polymorphisms and evaluate their associations with clinical data of breast carcinoma patients. METHODS: HRM analysis was designed to assess five single nucleotide polymorphisms (SNPs) in ABCB1 (rs2214102, rs1128503, rs2032582, rs2032583 and rs1045642) in genomic DNA from 103 breast carcinoma patients. Results were confirmed by direct DNA sequencing. RESULTS: HRM analysis revealed distinct patterns of melting curves for the respective genotypes of all followed SNPs. Sensitivity of HRM analysis compared with direct DNA sequencing was superior (97.1% vs. 93.9%). The overall accuracy of HRM was 97.6%. The coefficients of variation in replicate experiments encompassed the range 0.002%-0.038%. On the basis of the examined SNPs, one strong haplotype block containing rs2032582 and rs1128503 SNPs was identified. Significant associations of rs2032582 SNP with tumor size, negative HER-2/neu status, and family history of breast carcinoma were found. Patients carrying the ancestral homozygous genotype (GG) in rs2214102 had significantly worse progression-free survival in comparison with carriers of the non-ancestral allele (A) in the adjuvant set (p=0.005). CONCLUSIONS: A rapid, accurate, low-cost and time-effective method for screening ABCB1 SNPs was developed. Significant associations of ABCB1 rs2032582 and rs2214102 SNPs with prognostic factors and survival of patients were found.

• MeSH
• denaturace nukleových kyselin MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu diagnóza   genetika   terapie   MeSH
• P-glykoprotein genetika   MeSH
• P-glykoproteiny MeSH
• prognóza MeSH
• sekvenční analýza DNA metody   MeSH
• tranzitní teplota * MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABCB1 protein, human MeSH Prohlížeč
• P-glykoprotein MeSH
• P-glykoproteiny MeSH