Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex.
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.
Haenisch
S
S
Institute of Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany.
Zimmermann
U
U
Dazert
E
E
Wruck
C J
CJ
Dazert
P
P
Siegmund
W
W
Siegmund
S
S
Kroemer
H K
HK
Warzok
R W
RW
Cascorbi
I
I
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism*; D003001:Cloning, Molecular; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics*; D027361:Organic Anion Transporters / Q000096:biosynthesis / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics*; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D014162:Transfection
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004273:DNA, Neoplasm; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human