Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex

被引：132

作者：

Haenisch S. ^{[1
,4
]}

Zimmermann U. ^{[2
]}

Dazert E. ^{[3
]}

Wruck C.J. ^{[1
]}

Dazert P. ^{[4
]}

Siegmund S. ^{[4
]}

Kroemer H.K. ^{[4
]}

Warzok R.W. ^{[3
]}

Cascorbi I. ^{[1
,4
]}

机构：

[1] Institute of Pharmacology, University Hospital Schleswig-Holstein, Kiel

[2] Department of Urology, University of Greifswald, Greifswald

[3] Institute of Pathology, University of Greifswald, Greifswald

[4] Institute of Pharmacology, University of Greifswald, Greifswald

来源：

The Pharmacogenomics Journal | 2007年 / 7卷 / 1期

关键词：

ATP membrane transporter; P-glycoprotein; multidrug resistance; SNP; renal cell carcinoma; xenobiotics;

D O I：

10.1038/sj.tpj.6500403

中图分类号：

学科分类号：

摘要：

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.

引用

页码：56 / 65

页数：9

共 47 条

[1]

Borst P., Evers R., Kool M., Wijnholds J., The multidrug resistance protein family, Biochim Biophys Acta, 1461, pp. 347-357, (1999)

[2]

Klein I., Sarkadi B., Varadi A., An inventory of the human ABC proteins, Biochim Biophys Acta, 1461, pp. 237-262, (1999)

[3]

Konig J., Nies A.T., Cui Y., Leier I., Keppler D., Conjugate export pumps of the multidrug resistance protein (MRP) family: Localization, substrate specificity, and MRP2-mediated drug resistance, Biochim Biophys Acta, 1461, pp. 377-394, (1999)

[4]

Young A.M., Allen C.E., Audus K.L., Efflux transporters of the human placenta, Adv Drug Deliv Rev, 55, pp. 125-132, (2003)

[5]

Ambudkar S.V., Dey S., Hrycyna C.A., Ramachandra M., Pastan I., Gottesman M.M., Biochemical, cellular, and pharmacological aspects of the multidrug transporter, Annu Rev Pharmacol Toxicol, 39, pp. 361-398, (1999)

[6]

Schaub T.P., Kartenbeck J., Konig J., Vogel O., Witzgall R., Kriz W., Et al., Expression of the conjugate export pump encoded by the mrp2 gene in the apical membrane of kidney proximal tubules, J Am Soc Nephrol, 8, pp. 1213-1221, (1997)

[7]

Schaub T.P., Kartenbeck J., Konig J., Spring H., Dorsam J., Staehler G., Et al., Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma, J Am Soc Nephrol, 10, pp. 1159-1169, (1999)

[8]

Cui Y., Konig J., Buchholz J.K., Spring H., Leier I., Keppler D., Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug rsistance protein, MRP2, permanently expressed in human and canine cells, Mol Pharmacol, 55, pp. 929-937, (1999)

[9]

Juliano R.L., Ling V., A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants, Biochim Biophys Acta, 455, pp. 152-162, (1976)

[10]

Hoffmeyer S., Burk O., von Richter O., Arnold H.P., Brockmoller J., Johne A., Et al., Functional polymorphisms of the human multidrug-resitance gene: Multiple sequence variations and correlation of one allele with p-glycoprotein expression and activity in vivo, Proc Natl Acad Sci USA, 97, pp. 3473-3478, (2000)

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