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1.
Pharmacogenomics J ; 11(1): 25-34, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20351751

ABSTRACT

ABCC2 (MRP2) is an important export pump, expressed at tissue barriers. The genetic variants -24C>T, 1249G>A and 3972C>T are leading to inter-individual differences of bioavailability of various endogenous and exogenous compounds. Considering ABCC2 haplotypes, we investigated DNA-protein binding properties, mRNA secondary structure, mRNA stability, protein expression and transport activity in various cell lines and analyzed the bioavailability of talinolol in 24 healthy Caucasian volunteers; -24C>T had no clear influence on DNA-protein binding and the mRNA stability did not differ significantly. In transfected HEK293T/17 cells, haplotypes H9 (CGT), H10 (TGC) and H12 (TGT) had significantly lower protein expression, whereas H2 (CAC) exhibited significantly increased protein expression compared to the wild type (H1, CGC): 32.7 ± 8.8, 73.1 ± 6.3; 44.0 ± 15.5 and 115.2 ± 8.2%, respectively. This corresponded with efflux rates of the fluorescent dye glutathione-methylfluorescein in vitro and by trend with talinolol bioavailability in vivo. In conclusion our results show a haplotype-dependent influence on transport capacity of ABCC2, which seems to be mainly based on posttranscriptional modification of protein expression rather than transport rates.


Subject(s)
Gene Expression Regulation , Membrane Transport Proteins/genetics , Multidrug Resistance-Associated Proteins/genetics , RNA Processing, Post-Transcriptional , RNA, Messenger/genetics , Adrenergic beta-Antagonists/pharmacokinetics , Adult , Animals , Biological Availability , Caco-2 Cells , Cell Line, Transformed , Dogs , Female , Genetic Variation , HEK293 Cells , Haplotypes , Humans , Male , Membrane Transport Proteins/biosynthesis , Membrane Transport Proteins/metabolism , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/biosynthesis , Multidrug Resistance-Associated Proteins/metabolism , Polymorphism, Single Nucleotide , Propanolamines/pharmacokinetics , Protein Binding , RNA, Messenger/metabolism , Transfection , Young Adult
2.
Pharmacogenomics J ; 7(1): 56-65, 2007 Feb.
Article in English | MEDLINE | ID: mdl-16788565

ABSTRACT

There is increasing evidence that polymorphisms of the adenosine 5' triphosphate membrane transporters ABCB1 (P-glycoprotein, MDR1) may affect expression and function, whereas less information is available about the impact of ABCC2 (multidrug resistance-associated protein (MRP2)) single-nucleotide polymorphisms . Particularly, their role in human kidney for drug elimination and in the etiology of renal cell carcinoma is poorly understood. ABCB1 and ABCC2 mRNA and protein expression levels were determined by real-time polymerase chain reaction or immunohistochemistry in kidney cancer and adjacent unaffected cortex tissue of 82 nephrectomized renal cell cancer (RCC) patients (63 clear-cell RCC (CCRCC), 19 non-CCRCC). The DNA of all patients was genotyped for ABCB1 -2352G>A, -692T>C, 2677G>T/A (Ala893Ser/Thr), and 3435C>T, and ABCC2 -24C>T, 1249G>A (Val417Ile) and 3972C>T. ABCB1 and ABCC2 were less expressed in CCRCC than in normal cortex on mRNA as well as on protein level. Although the overall genotype frequency distribution did not differ between the patients and a matched control group, ABCB1 2677T/A and 3435T genotypes were associated with higher (P=0.02 and P=0.04) and ABCC2 -24 T with lower mRNA levels in normal tissues (0.03). The expression of ABCB1 and ABCC2 was not related to genetic variants in RCC tissue. In a reporter gene assay in HepG2 cells, the ABCC2 -24T construct showed an 18.7% reduced activity (P=0.003). In conclusion, ABCB1 and ABCC2 genotypes modulate the expression in the unaffected renal cortex of RCC patients, possibly contributing to inter-individual differences in drug and xenobiotics elimination. Their role in RCC cancer susceptibility or chemotherapy resistance needs further elucidation.


Subject(s)
Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Kidney Cortex/metabolism , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Membrane Transport Proteins/genetics , Multidrug Resistance-Associated Proteins/genetics , Organic Anion Transporters/genetics , RNA, Messenger/genetics , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Cloning, Molecular , DNA, Neoplasm/genetics , DNA, Neoplasm/isolation & purification , Female , Genes, Reporter/genetics , Genotype , Humans , Immunohistochemistry , Male , Membrane Transport Proteins/biosynthesis , Membrane Transport Proteins/metabolism , Middle Aged , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/biosynthesis , Organic Anion Transporters/biosynthesis , Polymorphism, Genetic/physiology , RNA, Neoplasm/genetics , RNA, Neoplasm/isolation & purification , Transfection
3.
Clin Pharmacol Ther ; 81(2): 228-34, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17192769

ABSTRACT

It is currently not clear whether the concentration-time curves of the immunosuppressants differ with respect to the CYP3A5, MDR1, or MRP2 genotype in dose-adapted stable kidney transplant patients. Dose/trough concentration ratios were obtained in 134 tacrolimus and 20 sirolimus-treated patients, and plasma concentration-time profiles were obtained from 16 (tacrolimus) and 10 (sirolimus) patients. Genotyping was carried out for CYP3A5 6986A>G; ABCB1 2677G>T/A, 3435C>T and ABCC2 -24C>T; 1249G>A; 3972C>T. Dose/trough concentration ratios were 0.67+/-0.3 and 1.36+/-0.73 x 10(3) l (P<0.00001) for tacrolimus and 0.42+/-0.17 and 0.84+/-0.46 x 10(3) l (P=0.18) for sirolimus in CYP3A5 non-expressors and expressors. The unadjusted tacrolimus area under curve (AUC)(0-12) was 106.8+/-17.5 ng/ml x h compared with 133.3+/-42.2 ng/ml x h (P=0.37) without affecting serum creatinine. Mean unadjusted AUC(0-24) of sirolimus did not differ significantly either. Therefore, CYP3A5 expressor status and not transporter variants is a main determinant of oral clearance, particularly for tacrolimus. Dose adaptation according to trough levels, however, appears to be sufficient to maintain similar concentration-time profiles.


Subject(s)
Cytochrome P-450 Enzyme System/genetics , Kidney Transplantation , Sirolimus/pharmacokinetics , Tacrolimus/pharmacokinetics , Adult , Aged , Area Under Curve , Biological Availability , Calcium Channel Blockers/metabolism , Calcium Channel Blockers/pharmacokinetics , Calcium Channel Blockers/therapeutic use , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/metabolism , Drug Therapy, Combination , Female , Genetic Variation , Genotype , Half-Life , Humans , Immunosuppressive Agents/metabolism , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Multidrug Resistance-Associated Protein 2 , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/metabolism , Mycophenolic Acid/pharmacokinetics , Mycophenolic Acid/therapeutic use , Prednisolone/metabolism , Prednisolone/pharmacokinetics , Prednisolone/therapeutic use , Sirolimus/metabolism , Sirolimus/therapeutic use , Tacrolimus/metabolism , Tacrolimus/therapeutic use
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