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¹ Departments of Medical Biochemistry, ² Surgery and Science, ³ Preventive Medicine, ⁴ Obstetrics and Gynecology, Graduate School of Medical Science, ⁵ Division of Genomic Analysis, Research Center for Genomic Information, Kyushu University, Fukuoka, Japan; ⁶ Coloproctology Center, Takano Hospital, Kumamoto, Japan; ⁷ Department of Surgery I, Faculty of Medicine, Gunma University, Maebashi, Japan; ⁸ Research Center for Innovative Cancer Therapy, Kurume, Japan

Requests for Reprints: Morimasa Wada, Department of Medical Biochemistry, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Phone: 81-92-642-6100; Fax: 81-92-642-6203. E-mail: wada{at}biochem1.med.kyushu-u.ac.jp

The multidrug resistance 1 (MDR1) is a key molecule in determining not only the resistance of cancer cells to anticancer agents but also the disposition of a variety of drugs in intestinal and other tissues. However, the mechanism underlying interindividual variations in levels of MDR1 activity and expression in various tissues remains unclear. We analyzed the nucleotide sequence polymorphisms in the 5' upstream regulatory region of the gene spanning 4 kb from the transcriptional start site of MDR1 and tried to identify any associations between polymorphisms and MDR1 expression. Within that region, we identified eight single nucleotide polymorphisms (SNPs) in the region in the Japanese population. Of the SNPs identified, -2410T>C, -1910T>C, and 692T>C were in perfect linkage disequilibrium. In normal colorectal mucosa, diplotypes at the region showed more significant association with the expression level of MDR1 mRNA than each SNP did. In an in vitro reporter assay, transcription activity of the minor-type construct carrying haplotypes 2 and 3 was significantly lower than that of the major-type construct carrying haplotype 1. We next identified two DNA binding proteins: one protein bound to the nucleotide sequence carrying -692T but not to that carrying -692C and another bound to the nucleotide sequence carrying -2352G but three times weaker than that carrying -2352A. This suggested the significance of SNP at -692 and -2352 of MDR1 in variable expression in the colon interindividually. This is the first report connecting SNPs and interindividual variety of MDR1 expression rationally.

Grant support: Grant-in-Aid for Cancer Research, Scientific Research on Priority Areas (C) "Medical Genome Science" and Scientific Research on Priority Areas (B) "Biological Transport Nano-Machine: Structure, Function, and Regulation" from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

Received 6/ 6/03; revised 9/22/03; accepted 10/ 1/03.

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