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Ulrich Brinkmann

Publications and source records attributed to Ulrich Brinkmann.

At least 19 recordsLinked to original sources
PubMed2022

A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder.

PURPOSE: Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs). METHODS: Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants. RESULTS: DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2. CONCLUSION: We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.

Adenosine Diphosphate↗
PubMed2006

Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway.

A genome-wide phenotype screen was used to identify factors and pathways that induce proliferation of human umbilical vein endothelial cells (HUVEC). HUVEC proliferation is a recognized marker for factors that modulate vascularization. Screening "hits" included known proangiogenic factors, such as VEGF, FGF1, and FGF2 and additional factors for which a direct association with angiogenesis was not previously described. These include the kinase TBK1 as well as Toll-like receptor adaptor molecule and IFN regulatory factor 3. All three proteins belong to one signaling pathway that mediates induction of gene expression, including a mixture of secreted factors, which, in concert, mediate proliferative activity toward endothelial cells. TBK1 as the "trigger" of this pathway is induced under hypoxic conditions and expressed at significant levels in many solid tumors. This pattern of expression and the decreased expression of angiogenic factors in cultured cells upon RNA-interference-mediated ablation suggests that TBK1 is important for vascularization and subsequent tumor growth and a target for cancer therapy.

Adaptor Proteins, Vesicular Transport↗
PubMed2005

Common denominator procedure: a novel approach to gene-expression data mining for identification of phenotype-specific genes.

MOTIVATION: We have established a novel data mining procedure for the identification of genes associated with pre-defined phenotypes and/or molecular pathways. Based on the observation that these genes are frequently expressed in the same place or in close proximity at about the same time, we have devised an approach termed Common Denominator Procedure. One unusual feature of this approach is that the specificity and probability to identify genes linked to the desired phenotype/pathway increase with greater diversity of the input data. RESULT: To show the feasibility of our approach, the Cancer Genome Anatomy Project expression data combined with a defined set of angiogenic factors was used to identify additional and novel angiogenesis-associated genes. A multitude of these additional genes were known to be associated with angiogenesis according to published data, verifying our approach. For some of the remaining candidate genes, application of a high-throughput functional genomics platform (XantoScreen) provided further experimental evidence for association with angiogenesis.

Angiogenic Proteins↗
PubMed2005

High throughput functional genomics: identification of novel genes with tumor suppressor phenotypes.

We have used a combination of high throughput functional genomics, computerized database mining and expression analyses to discover novel human tumor suppressor genes (TSGs). A genome-wide high throughput cDNA phenotype screen was established to identify genes that induce apoptosis or reduce cell viability. TSGs are expressed in normal tissue and frequently act by reduction of growth of transformed cells or induce apoptosis. In agreement with that and thus serving as platform validation, our pro-apoptotic hits included genes for which tumor suppressing activities were known, such as kangai1 and CD81 antigen. Additional genes that so far have been claimed as putative TSGs or associated with tumor inhibitory activities (prostate differentiation factor, hRAS-like suppressor 3, DPH2L1-like and the metastasis inhibitor Kiss1) were confirmed in their proposed TSG-like phenotype by functionally defining their growth inhibitory or pro-apoptotic function towards cancer cells. Finally, novel genes were identified for which neither association with cell growth nor with apoptosis were previously described. A subset of these genes show characteristics of TSGs because they (i) reduce the growth or induce apoptosis in tumor cells; (ii) show reduced expression in tumor vs. normal tissue; and (iii) are located on chromosomal (LOH-) loci for which cancer-associated deletions are described. The pro-apoptotic phenotype and differential expression of these genes in normal and malignant tissue make them promising target candidates for the diagnosis and therapy of various tumors.

Apoptosis↗
PubMed2004

High-throughput functional genomics identifies genes that ameliorate toxicity due to oxidative stress in neuronal HT-22 cells: GFPT2 protects cells against peroxide.

We describe a novel genetic screen that is performed by transfecting every individual clone of an expression clone collection into a separate population of cells in a high-throughput mode. We combined high-throughput functional genomics with experimental validation to discover human genes that ameliorate cytotoxic responses of neuronal HT-22 cells upon exposure to oxidative stress. A collection of 5,000 human cDNAs in mammalian expression vectors were individually transfected into HT-22 cells, which were then exposed to H(2)O(2). Five genes were found that are known to be involved in pathways of detoxification of peroxide (catalase, glutathione peroxidase-1, peroxiredoxin-1, peroxiredoxin-5, and nuclear factor erythroid-derived 2-like 2). The presence of those genes in our "hit list" validates our screening platform. In addition, a set of candidate genes was found that has not been previously described as involved in detoxification of peroxide. One of these genes, which was consistently found to reduce H(2)O(2) -induced toxicity in HT-22, was GFPT2. This gene is expressed at significant levels in the central nervous system (CNS) and encodes glutamine-fructose-6-phosphate transaminase (GFPT) 2, a rate-limiting enzyme in hexosamine biosynthesis. GFPT has recently also been shown to ameliorate the toxicity of methylmercury in Saccharomyces cerevisiae. Methylmercury causes neuronal cell death in part by protein modification as well as enhancing the production of reactive oxygen species (ROS). The protective effect of GFPT2 against H(2)O(2) toxicity in neuronal HT-22 cells may be similar to its protection against methylmercury in yeast. Thus, GFPT appears to be conserved among yeast and men as a critical target of methylmercury and ROS-induced cytotoxicity.

Animals↗
PubMed2004

Development of secreted proteins as biotherapeutic agents.

As one of the most important classes of proteins, secreted factors account for about one-tenth of the human genome, 3000 - 4000 in total, including factors of signalling pathways, blood coagulation and immune defence, as well as digestive enzymes and components of the extracellular matrix. Secreted proteins are a rich source of new therapeutics and drug targets, and are currently the focus of major drug discovery programmes throughout the industry. Many of the most important novel drugs developed in biotechnology have resulted from the application of secreted proteins as therapeutics. Secreted proteins often circulate throughout the body and, therefore, have access to most organs and tissues. Because of that, many of the factors are themselves therapeutic agents. This paper gives an overview on the features and functions of human secreted proteins and peptides, as well as strategies by which to discover additional therapeutic proteins from the human 'secretome'. Furthermore, a variety of examples are provided for the therapeutic use of recombinant secreted proteins as 'biologicals', including features and applications of recombinant antibodies, erythropoietin, insulin, interferon, plasminogen activators, growth hormone and colony-stimulating factors.

Drug Design↗
PubMed2003

Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1.

BACKGROUND: One third of patients with epilepsy have drug-resistant epilepsy, which is associated with an increased risk of death and debilitating psychosocial consequences. Because this form is resistant to multiple antiepileptic drugs, the mode of resistance must be nonspecific, involving drug-efflux transporters such as ATP-binding cassette sub-family B member 1 (ABCB1, also known as MDR1 and P-glycoprotein 170). We hypothesized that the CC genotype at the ABCB1 C3435T polymorphism, which is associated with increased expression of the protein, influences the response to antiepileptic-drug treatment. METHODS: ABCB1 3435 was genotyped in 315 patients with epilepsy, classified as drug-resistant in 200 and drug-responsive in 115, and 200 control subjects without epilepsy. Recently devised methods were used to control for population stratification, and linkage disequilibrium was calculated across the gene. RESULTS: As compared with patients with drug-responsive epilepsy, patients with drug-resistant epilepsy were more likely to have the CC genotype at ABCB1 3435 than the TT genotype (odds ratio, 2.66; 95 percent confidence interval, 1.32 to 5.38; P=0.006). There was no genetic stratification between the two groups of patients. The polymorphism fell within an extensive block of linkage disequilibrium spanning much or all of the gene, implying that the polymorphism may not itself be causal but rather may be linked with the causal variant. CONCLUSIONS: These pharmacogenomic results identify a genetic factor associated with resistance to antiepileptic drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Digoxin pharmacokinetics and MDR1 genetic polymorphisms.

BACKGROUND: The effect of MDR1 C3435T single nucleotide polymorphism (SNP) in exon 26 on digoxin pharmacokinetics has recently been challenged. OBJECTIVE. To clarify the relationships between MDR1 genetic polymorphisms in exon 26 (C3435T) and 21 (G2677T/A) and digoxin pharmacokinetics. MATERIALS AND METHODS: MDR1 genotypes for C3435T and G2677T/A SNPs were determined in 32 healthy subjects whose single oral dose digoxin pharmacokinetics had been measured over 48 h. RESULTS: A significant relationship was observed between C3435T SNP and digoxin AUCs ( p<0,05). Homozygous TT subjects had 20% higher digoxin plasma concentrations than CT and CC subjects and a trend for higher 48 h digoxin urinary recoveries (TT>CT>CC). Similar results, although not statistically significant, were observed from the MDR1 G2677T/A SNP. CONCLUSIONS: Our results confirm that the MDR1 C3435T single nucleotide polymorphism (SNP) significantly affects digoxin disposition kinetics, with homozygous TT subjects presenting the highest plasma concentrations.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Expression and localization of the multidrug resistance protein 5 (MRP5/ABCC5), a cellular export pump for cyclic nucleotides, in human heart.

The multidrug resistance protein 5 (MRP5/ABCC5) has been recently identified as cellular export pump for cyclic nucleotides with 3',5'-cyclic GMP (cGMP) as a high-affinity substrate. In view of the important role of cGMP for cardiovascular function, expression of this transport protein in human heart is of relevance. We analyzed the expression and localization of MRP5 in human heart [21 auricular (AS) and 15 left ventricular samples (LV) including 5 samples of dilated and ischemic cardiomyopathy]. Quantitative real-time polymerase chain reaction normalized to beta-actin revealed expression of the MRP5 gene in all samples (LV, 38.5 +/- 12.9; AS, 12.7 +/- 5.6; P < 0.001). An MRP5-specific polyclonal antibody detected a glycoprotein of approximately 190 kd in crude cell membrane fractions from these samples. Immunohistochemistry with the affinity-purified antibody revealed localization of MRP5 in cardiomyocytes as well as in cardiovascular endothelial and smooth muscle cells. Furthermore, we could detect MRP5 and ATP-dependent transport of [(3)H]cGMP in sarcolemma vesicles of human heart. Quantitative analysis of the immunoblots indicated an interindividual variability with a higher expression of MRP5 in the ischemic (104 +/- 38% of recombinant MRP5 standard) compared to normal ventricular samples (53 +/- 36%, P < 0.05). In addition, we screened genomic DNA from our samples for 20 single-nucleotide polymorphisms in the MRP5 gene. These results indicate that MRP5 is localized in cardiac and cardiovascular myocytes as well as endothelial cells with increased expression in ischemic cardiomyopathy. Therefore, MRP5-mediated cellular export may represent a novel, disease-dependent pathway for cGMP removal from cardiac cells.

Aged↗
PubMed2003

Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis.

BACKGROUND & AIMS: The human multidrug resistance 1 (MDR1) gene product P-glycoprotein is highly expressed in intestinal epithelial cells, where it constitutes a barrier against xenobiotics. The finding that mdr1a knockout mice develop a form of colitis that is similar to ulcerative colitis, which can be prevented by antibiotics, indicates a barrier function for P-glycoprotein against the invasion of bacteria or toxins. Because the MDR1 single nucleotide polymorphism C3435T is associated with lower intestinal P-glycoprotein expression, we tested whether this polymorphism predisposes to development of ulcerative colitis. METHODS: Allele frequencies and genotype distributions of the C3435T single nucleotide polymorphism were investigated in 149 patients with ulcerative colitis, 126 patients with Crohn's disease, and sex-matched healthy controls. RESULTS: Significantly increased frequencies of the 3435T allele and the 3435TT genotype were observed in patients with ulcerative colitis compared with controls (3435T: P = 0.049; odds ratio, 1.4; 95% confidence interval, 1.02-1.94; 3435TT: P = 0.045; odds ratio, 2.03; 95% confidence interval, 1.04-3.95). In contrast, frequencies of the T allele and the TT genotype were the same in patients with Crohn's disease as in controls (P = 0.66 and P = 0.59, respectively). In comparison to 998 non-sex-matched controls, the effect for the TT genotype in ulcerative colitis patients was more pronounced (P = 0.0055; odds ratio, 2.1). CONCLUSIONS: The higher frequency of the 3435TT genotype in patients with ulcerative colitis corroborates the findings from the mdr1a knockout mice. The results support the notion that P-glycoprotein plays a major role in the defense against intestinal bacteria or toxins. Impairment of barrier function in 3435TT subjects could render this genotype more susceptible to the development of ulcerative colitis.

Adolescent↗
PubMed2003

Dipyridamole enhances digoxin bioavailability via P-glycoprotein inhibition.

BACKGROUND: On the basis of in vitro studies indicating that dipyridamole is an inhibitor for the MDR1 efflux membrane transporter P-glycoprotein, we postulated that dipyridamole could increase the bioavailability of digoxin, a P-glycoprotein substrate. OBJECTIVES: The main objective was to determine whether dipyridamole alters the bioavailability of digoxin. The secondary objective was to determine whether the magnitude of the pharmacokinetic interaction was influenced by MDR1 genetic polymorphism in exon 26 (C3435T). MATERIAL AND METHODS: (1) The effect of dipyridamole on in vitro P-glycoprotein-mediated, polarized transport of tritium-labeled digoxin was investigated in Caco-2 cell monolayers. (2) Twelve healthy volunteers participated in this open, randomized, 2-period crossover study, in which the effects of dipyridamole (300 mg/d for 3 days) versus placebo on the pharmacokinetics of a single oral dose of digoxin (0.5 mg) were compared. MDR1 genotyping (exon 26, C3435T) was determined before the study to include 6 homozygous CC and 6 homozygous TT subjects. RESULTS: Dipyridamole inhibited [(3)H]digoxin transport in Caco-2 cells with a 50% inhibitory concentration value of 1.5 +/- 1.5 micromol/L. We observed a 20% and 13% increase in digoxin area under the plasma concentration-time curve (AUC) from 0 to 4 hours and AUC from 0 to 24 hours (P <.05), respectively, during dipyridamole administration, which was consecutive to an increase in digoxin absorption. Digoxin AUC from 0 to 4 hours and AUC from 0 to 24 hours were significantly higher among subjects harboring the TT compared with the CC MDR1 genotype: 7.5 +/- 1.2 ng x h x mL(-1) versus 6.1 +/- 0.8 ng x h x mL(-1) and 20.2 +/- 2.1 ng x h x mL(-1) versus 16.8 +/- 1.7 ng x h x mL(-1), respectively (P <.05). Digoxin pharmacokinetic modifications during the dipyridamole period were similar in both genotypes. CONCLUSION: Dipyridamole is an in vitro and in vivo P-glycoprotein inhibitor that increases intestinal digoxin absorption and digoxin plasma concentrations. In light of the modest changes in digoxin pharmacokinetics in the presence of dipyridamole, this drug interaction is probably clinically irrelevant.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Sequence diversity and functional characterization of the 5'-regulatory region of human CYP2C19.

Cytochrome p4502C19 (CYP2C19) plays an important role in drug biotransformation and has been shown to be genetically polymorphic. While polymorphisms in the coding region that have large effects on activity are well described, until recently, a lack of knowledge of the promoter sequence has hindered efforts to study it. Genetic variants in the promoter region have not been described and factors that influence its gene expression via promotor regulation remain largely undefined. We have cloned and sequenced 1.8 kb of the human CYP2C19 promoter. This promoter contains a number of putative transcription factor sites, including HepG2-specific factor 1, glucocorticoid response element, estrogen receptor element, constitutive androstane receptor and peroxisome proliferator-activated receptor. Sequencing of DNA obtained from 67 individuals identified eight single nucleotide polymorphisms within this region. No sequence of a known human pregnane X receptor response element was found in this section of the CYP2C19 promoter, despite the known effect of rifampin on the expression of this gene. A plasmid containing the 1.8-kb CYP2C19 promoter coupled to a luciferase reporter gene has been constructed and demonstrated to be functional and sensitive to induction by omeprazole in HuH7 cells. Nested deletions of CYP2C19 promoter were generated and the ability of serial promoter deletion constructs to activate luciferase expression in the HepG2 cell line was analysed. These data make possible future studies to elucidate the molecular mechanisms by which CYP2C19 can be induced in clinical settings and the consequences of genetic variability in its promoter.

Amino Acid Sequence↗
PubMed2002

Functional polymorphisms of the human multidrug resistance (MDR1) gene: correlation with P glycoprotein expression and activity in vivo.

The human MDR1 gene encodes an integral membrane protein, P glycoprotein (Pgp), whose function is the energy dependent export of substances from the inside of cells, and from membranes, to the outside. Its physiological role is the protection of cells from toxic substances or metabolites. Many drugs that have been developed for the treatment of human diseases are substrates of Pgp. Because of that, the degree of expression and the functionality of the MDR1 gene product can directly affect the therapeutic effectiveness of such agents. This is of particular importance in cancer therapy where high expression and activity of MDR1 causes cancer cells to become refractory to the treatment with many agents, all of which are Pgp substrates. MDR1 is also expressed on different non-malignant cells in various organs, e.g. in the intestine and at the blood brain barrier. Modulation of MDR1 expression in these normal cell types can also influence the activity and bioavailability of drugs. In the intestine, modulation of MDR1 may control the degree of drug uptake following drug ingestion. At the blood-brain barrier, Pgp may influence the uptake of substrates into the brain: high Pgp levels may limit the uptake of sufficient amounts of desired drugs into the brain, and reduced Pgp activity could lead to abnormally increased accumulation in the brain and undesired side effects of drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine.

AIMS: The C3435T polymorphism in the human MDR1 gene is associated with lower intestinal P-glycoprotein expression, reduced protein function in peripheral blood cells and higher plasma concentrations of the P-glycoprotein substrate digoxin. Using fexofenadine, a known P-glycoprotein substrate, the hypothesis was tested whether this polymorphism also affects the disposition of other drugs in humans. METHODS: Ten Caucasian subjects homozygous for the wild-type allele at position 3435 (CC) and 10 individuals homozygous for T at position 3435 participated in this study. A single oral dose of 180 mg fexofenadine HCl was administered. Plasma and urine concentrations of fexofenadine were measured up to 72 h using a sensitive LC/MS method. In addition, P-glycoprotein function was assessed using efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ cells. Results Fexofenadine plasma concentrations varied considerably among the study population. However, fexofenadine disposition was not significantly different between the CC and TT groups (e.g. AUC(0,infinity) CC vs TT: 3567.1+/-1535.5 vs 3910.1+/-1894.8 ng ml-1 h, NS; 95% CI on the difference -1364.9, 2050.9). In contrast, P-glycoprotein function was significantly decreased in CD56+ cells of the TT compared with the CC group (rhodamine fluorescence CC vs TT: 45.6+/-7.2% vs 61.1+/-12.3%, P<0.05; 95% CI on the difference 5.6, 25.5). Conclusions In spite of MDR1 genotype-dependent differences in P-glycoprotein function in peripheral blood cells, there was no association of the C3435T polymorphism with the disposition of the P-glycoprotein substrate fexofenadine in this German Caucasian study population. These data indicate that other mechanisms including uptake transporter function are likely to play a role in fexofenadine disposition.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene.

OBJECTIVE: We investigated the effect of polymorphisms in the P-glycoprotein (P-gp) MDR1 gene on steady-state pharmacokinetics of digoxin in Caucasians. According to earlier data, homozygous TT of the exon 26 complementary deoxyribonucleic acid (cDNA) 3435C>T polymorphism was associated with low P-gp expression in the human intestine. METHODS: Eight healthy male homozygous carriers of the wild-type exon-26 3435C>T (CC), 8 heterozygous subjects (CT), and 8 homozygous mutant (TT) subjects were selected. Seven further MDR1 polymorphisms were determined. Digoxin was administered orally twice daily on the first two study days; on days 3 to 5, 0.25 mg was given in the morning. On day 5, kinetic parameters were analyzed for genotype-phenotype and haplotype-phenotype relationships. RESULTS: The area under the plasma concentration-time curve from time zero to 4 hours [AUC(0-4)] (P =.042) and C(max) (P =.043) values of digoxin were higher in subjects with the 3435TT genotype than in those with the 3435CC. No influence of other single nucleotide polymorphisms (SNPs) on digoxin parameters was detected. Comparison of genotypes deduced from SNPs 2677G>T (exon 21) and 3435C>T revealed significant differences for AUC(0-4) (P =.034) and C(max) (P =.039), which were substantiated by haplotype analysis. Haplotype 12 (2677G/3435T), which had a frequency of 13.3% in a randomly drawn Caucasian sample (n = 687), was associated (Mann-Whitney test) with higher AUC(0-4) values (P =.009) than were found in noncarriers (mean +/- SD, 5.7 +/- 0.9 microg. h/L [n = 7] versus 4.8 +/- 0.9 microg. h/L [n = 17]). Haplotype 11 (2677G/3435C) had lower AUC(0-4) values (P =.013) compared with those of noncarriers (mean +/- SD, 4.7 +/- 0.9 microg. h/L [n = 16] versus 5.6 +/- 0.9 microg. h/L [n = 8]). Results of haplotype analysis match data of other MDR1 studies. CONCLUSION: Haplotype 12 codes for high values of AUC(0-4) and C(max) of orally administered digoxin. Analysis of MDR1 haplotypes is superior to unphased SNP analysis to predict MDR1 phenotype.

Animals↗
PubMed2002

Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences.

By systematic mutation screening of the polyspecific organic cation transporter hOCT1 (SLC22A1) in 57 Caucasians, 25 genetic variations were identified and further analysed for population frequency. Five mutations resulting in the amino acid changes Arg61Cys, Cys88Arg, Phe160Leu, Gly401Ser, and Met420del, with respective allele frequencies of 9.1, 0.6, 22, 3.2, and 16%, were functionally characterized upon expression in Xenopus oocytes. Phe160Leu and Met420del exhibited substrate affinities and selectivites identical to hOCT1 wild-type. In contrast, uptake of 0.1 microm [3H]1-methyl-4-phenylpyridinium ([3H]MPP) by Arg61Cys, Cys88Arg and Gly401Ser were reduced to 30, 1.4 and 0.9% compared to wild-type, respectively. Since transport of 1 microm [3H]serotonin by Cys88Arg and Gly401Ser was reduced to only 13 and 12% of wild-type, these mutants exhibit a changed substrate selectivity. The data show that the mutants Arg61Cys, Cys88Arg and Gly401Ser could affect the disposition of OCT1 substrates and as a consequence may alter the duration and intensity of effects of drugs and neurotransmitters which are substrates for hOCT1.

Adult↗
PubMed2002

Association of the P-glycoprotein transporter MDR1(C3435T) polymorphism with the susceptibility to renal epithelial tumors.

Except for hereditary disease, genetic factors that contribute to the development of renal epithelial tumors are unknown. There is a possibility that the MDR1 encoded plasma membrane transporter P-glycoprotein (PGP) influences the risk of development of renal neoplasms. PGP is known to be involved in uptake, binding, transport, and distribution of xenobiotics. There is evidence that the MDR1(C3435T) polymorphism drives expression and modulates disease risk. In an explorational case-control study, constitutional genotype frequencies were established at MDR1(C3435T) of 537 healthy control subjects and compared with those of 212 patients with renal epithelial tumors. There were 179 clear cell renal cell carcinoma (CCRCC) and 33 tumors collectively assigned as non-CCRCC. In a second study, genotypes of another 150 healthy control subjects and 50 patients with three non-CCRCC types (26 papillary RCC, 11 chromophobe RCC, and 13 renal oncocytic adenoma) were compared. PCR-restriction fragment length polymorphism-based analysis of constitutional DNA, and statistical analysis were applied. PGP expression was analyzed by quantitative immunohistochemistry. The explorational study showed a significant association between T allele frequency and the occurrence of tumors (P = 0.007). When tumors were histopathologically distinguished into frequent CCRCC and less frequent non-CCRCC, both patient groups contributed to this effect with a seemingly strong influence by the latter (P = 0.0419). The second study established the T allele as a risk factor especially for non-CCRCC (P = 0.0005) with the highest risk for homozygote TT allele carriers (P < 0.0001). Independently, MDR1(C3435T) genotype associated variations in PGP expression were shown in normal renal parenchyma with a 1.5-fold difference of median values (TT, 1.9; CC, 2.8; P = 0.0065). The data provide evidence for PGP to influence the susceptibility to develop renal epithelial tumors by virtue of its MDR1(C3435T) polymorphism and changes in expression. Especially T and TT carriers are at risk for developing non-CCRCC, i.e., papillary and chromophobe RCC as well as oncocytic adenomas.

ATP Binding Cassette Transporter, Subfamily B, Mem↗