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Polymorphisms of SLC22A9 (hOAT7) in Korean Females with Osteoporosis

  • Ahn, Seong Kyu (Department of Tropical Medicine and Parasitology, College of Medicine, Inha University) ;
  • Suh, Chang Kook (Department of Physiology and Biophysics, College of Medicine, Inha University) ;
  • Cha, Seok Ho (Department of Tropical Medicine and Parasitology, College of Medicine, Inha University)
  • 투고 : 2015.01.21
  • 심사 : 2015.03.05
  • 발행 : 2015.07.01

초록

Among solute carrier proteins, the organic anion transporters (OATs) play an important role for the elimination or reabsorption of endogenous and exogenous negatively charged anionic compounds. Among OATs, SLC22A9 (hOAT7) transports estrone sulfate with high affinity. The net decrease of estrogen, especially in post-menopausal women induces rapid bone loss. The present study was performed to search the SNP within exon regions of SLC22A9 in Korean females with osteoporosis. Fifty healthy controls and 50 osteoporosis patients were screened for the genetic polymorphism in the coding region of SLC22A9 using GC-clamped PCR and denaturing gradient gel electrophoresis (DGGE). Six SNPs were found on the SLC22A9 gene from Korean women with/without osteoporosis. The SNPs were located as follows: two SNPs in the osteoporosis group (A645G and T1277C), three SNPs in the control group (G1449T, C1467T and C1487T) and one SNP in both the osteoporosis and control groups (G767A). The G767A, T1277C and C1487T SNPs result in an amino acid substitution, from synonymous vs nonsynonymous substitution arginine to glutamine (R256Q), phenylalanine to serine (F426S) and proline to leucine (P496L), respectively. The Km values and Vmax of the wild type, R256Q, P496L and F426S were 8.84, 8.87, 9.83 and $12.74{\mu}M$, and 1.97, 1.96, 2.06 and 1.55 pmol/oocyte/h, respectively. The present study demonstrates that the SLC22A9 variant F426S is causing inter-individual variation that is leading to the differences in transport of the steroid sulfate conjugate (estrone sulfate) and, therefore this could be used as a marker for certain disease including osteoporosis.

키워드

참고문헌

  1. Riggs BL, Khosla S, Melton LJ 3rd. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev. 2002;23:279-302. https://doi.org/10.1210/edrv.23.3.0465
  2. Bonjour JP, Theintz G, Law F, Slosman D, Rizzoli R. Peak bone mass: facts and uncertainties. Arch Pediatr. 1995;2:460-468. https://doi.org/10.1016/0929-693X(96)81183-3
  3. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423:337-342. https://doi.org/10.1038/nature01658
  4. Wang FS, Ko JY, Lin CL, Wu HL, Ke HJ, Tai PJ. Knocking down dickkopf-1 alleviates estrogen deficiency induction of bone loss. A histomorphological study in ovariectomized rats. Bone. 2007;40:485-492. https://doi.org/10.1016/j.bone.2006.09.004
  5. Muir M, Romalo G, Wolf L, Elger W, Schweikert HU. Estrone sulfate is a major source of local estrogen formation in human bone. J Clin Endocrinol Metab. 2004;89:4685-4692. https://doi.org/10.1210/jc.2004-0049
  6. Slemenda CW, Longcope C, Zhou L, Hui SL, Peacock M, Johnston CC. Sex steroids and bone mass in older men. Positive associations with serum estrogens and negative associations with androgens. J Clin Invest. 1997;100:1755-1759. https://doi.org/10.1172/JCI119701
  7. Khosla S, Melton LJ 3rd, Atkinson EJ, O'Fallon WM, Klee GG, Riggs BL. Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J Clin Endocrinol Metab. 1998;83:2266-2274.
  8. Compston JE. Sex steroids and bone. Physiol Rev. 2001;81:419-447. https://doi.org/10.1152/physrev.2001.81.1.419
  9. Hui SL, Perkins AJ, Zhou L, Longcope C, Econs MJ, Peacock M, McClintock C, Johnston CC Jr. Bone loss at the femoral neck in premenopausal white women: effects of weight change and sex-hormone levels. J Clin Endocrinol Metab. 2002;87:1539-1543. https://doi.org/10.1210/jcem.87.4.8393
  10. Noel CT, Reed MJ, Jacobs HS, James VH. The plasma concentration of oestrone sulphate in postmenopausal women: lack of diurnal variation, effect of ovariectomy, age and weight. J Steroid Biochem. 1981;14:1101-1105. https://doi.org/10.1016/0022-4731(81)90039-X
  11. Roberts KD, Rochefort JG, Bleau G, Chapdelaine A. Plasma estrone sulfate levels in postmenopausal women. Steroids. 1980;35:179-187. https://doi.org/10.1016/0039-128X(80)90101-4
  12. Hawkins RA, Oakey RE. Estimation of oestrone sulphate, oestradiol-17beta and oestrone in peripheral plasma: concentrations during the menstrual cycle and in men. J Endocrinol. 1974;60:3-17. https://doi.org/10.1677/joe.0.0600003
  13. Cha SH, Sekine T, Fukushima JI, Kanai Y, Kobayashi Y, Goya T, Endou H. Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001;59:1277-1286. https://doi.org/10.1124/mol.59.5.1277
  14. Shin HJ, Anzai N, Enomoto A, He X, Kim do K, Endou H, Kanai Y. Novel liver-specific organic anion transporter OAT7 that operates the exchange of sulfate conjugates for short chain fatty acid butyrate. Hepatology. 2007;45:1046-1055. https://doi.org/10.1002/hep.21596
  15. Cha SH, Sekine T, Kusuhara H, Yu E, Kim JY, Kim DK, Sugiyama Y, Kanai Y, Endou H. Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J Biol Chem. 2000;275:4507-4512. https://doi.org/10.1074/jbc.275.6.4507
  16. Deighton CM, Walker DJ, Griffiths ID, Roberts DF. The contribution of HLA to rheumatoid arthritis. Clin Genet. 1989;36:178-182.
  17. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356-361. https://doi.org/10.1038/nature01661
  18. Klareskog L, Padyukov L, Lorentzen J, Alfredsson L. Mechanisms of disease: Genetic susceptibility and environmental triggers in the development of rheumatoid arthritis. Nat Clin Pract Rheumatol. 2006;2:425-433. https://doi.org/10.1038/ncprheum0249
  19. Masi AT, Aldag JC, Chatterton RT. Sex hormones and risks of rheumatoid arthritis and developmental or environmental influences. Ann N Y Acad Sci. 2006;1069:223-235. https://doi.org/10.1196/annals.1351.020
  20. Lee WK, Kwak JO, Hwang JS, Suh CK, Cha SH. Identification and characterization of single nucleotide polymorphisms of SLC22A11 (hOAT4) in Korean women osteoporosis patients. Mol Cells. 2008;25:265-271.
  21. Mumm S, Jones J, Finnegan P, Henthorn PS, Podgornik MN, Whyte MP. Denaturing gradient gel electrophoresis analysis of the tissue nonspecific alkaline phosphatase isoenzyme gene in hypophosphatasia. Mol Genet Metab. 2002;75:143-153. https://doi.org/10.1006/mgme.2001.3283
  22. Wu Y, Hayes VM, Osinga J, Mulder IM, Looman MW, Buys CH, Hofstra RM. Improvement of fragment and primer selection for mutation detection by denaturing gradient gel electrophoresis. Nucleic Acids Res. 1998;26:5432-5440. https://doi.org/10.1093/nar/26.23.5432
  23. Van Orsouw NJ, Vijg J. Design and application of 2-D DGGEbased gene mutational scanning tests. Genet Anal. 1999;14:205-213. https://doi.org/10.1016/S1050-3862(98)00028-X
  24. Kwak JO, Kim HW, Oh KJ, Kim DS, Han KO, Cha SH. Co-localization and interaction of organic anion transporter 1 with caveolin-2 in rat kidney. Exp Mol Med. 2005;37:204-212. https://doi.org/10.1038/emm.2005.28
  25. Grumbach MM, Auchus RJ. Estrogen: consequences and implications of human mutations in synthesis and action. J Clin Endocrinol Metab. 1999;84:4677-4694.
  26. Bilezikian JP. Sex steroids, mice, and men: when androgens and estrogens get very close to each other. J Bone Miner Res. 2002;17:563-566. https://doi.org/10.1359/jbmr.2002.17.4.563
  27. Evseenko DA, Paxton JW, Keelan JA. ABC drug transporter expression and functional activity in trophoblast-like cell lines and differentiating primary trophoblast. Am J Physiol Regul Integr Comp Physiol. 2006;290:R1357-1365. https://doi.org/10.1152/ajpregu.00630.2005
  28. Evseenko DA, Murthi P, Paxton JW, Reid G, Emerald BS, Mohankumar KM, Lobie PE, Brennecke SP, Kalionis B, Keelan JA. The ABC transporter BCRP/ABCG2 is a placental survival factor, and its expression is reduced in idiopathic human fetal growth restriction. FASEB J. 2007;21:3592-3605. https://doi.org/10.1096/fj.07-8688com
  29. Briz O, Serrano MA, MacIas RI, Gonzalez-Gallego J, Marin JJ. Role of organic anion-transporting polypeptides, OATP-A, OATP-C and OATP-8, in the human placenta-maternal liver tandem excretory pathway for foetal bilirubin. Biochem J. 2003;371:897-905. https://doi.org/10.1042/bj20030034
  30. Patel P, Weerasekera N, Hitchins M, Boyd CA, Johnston DG, Williamson C. Semi quantitative expression analysis of MDR3, FIC1, BSEP, OATP-A, OATP-C,OATP-D, OATP-E and NTCP gene transcripts in 1st and 3rd trimester human placenta. Placenta. 2003;24:39-44. https://doi.org/10.1053/plac.2002.0879
  31. Ugele B, St-Pierre MV, Pihusch M, Bahn A, Hantschmann P. Characterization and identification of steroid sulfate transporters of human placenta. Am J Physiol Endocrinol Metab. 2003;284:E390-398. https://doi.org/10.1152/ajpendo.00257.2002
  32. Trauner M, Boyer JL. Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev. 2003;83:633-671. https://doi.org/10.1152/physrev.00027.2002
  33. Evseenko DA, Paxton JW, Keelan JA. Independent regulation of apical and basolateral drug transporter expression and function in placental trophoblasts by cytokines, steroids, and growth factors. Drug Metab Dispos. 2007;35:595-601. https://doi.org/10.1124/dmd.106.011478
  34. Wang H, Wu X, Hudkins K, Mikheev A, Zhang H, Gupta A, Unadkat JD, Mao Q. Expression of the breast cancer resistance protein (Bcrp1/Abcg2) in tissues from pregnant mice: effects of pregnancy and correlations with nuclear receptors. Am J Physiol Endocrinol Metab. 2006;291:E1295-1304. https://doi.org/10.1152/ajpendo.00193.2006
  35. Nozawa T, Minami H, Sugiura S, Tsuji A, Tamai I. Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab Dispos. 2005;33:434-439.
  36. Ho RH, Leake BF, Roberts RL, Lee W, Kim RB. Ethnicitydependent polymorphism in Na+-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition. J Biol Chem. 2004;279:7213-7222. https://doi.org/10.1074/jbc.M305782200
  37. Conrad S, Kauffmann HM, Ito K, Deeley RG, Cole SP, Schrenk D. Identification of human multidrug resistance protein 1(MRP1) mutations and characterization of a G671V substitution. J Hum Genet. 2001;46:656-663. https://doi.org/10.1007/s100380170017
  38. Lee SS, Jeong HE, Yi JM, Jung HJ, Jang JE, Kim EY, Lee SJ, Shin JG. Identification and functional assessment of BCRP polymorphisms in a Korean population. Drug Metab Dispos. 2007;35:623-632. https://doi.org/10.1124/dmd.106.012302
  39. Keitel V, Nies AT, Brom M, Hummel-Eisenbeiss J, Spring H, Keppler D. A common Dubin-Johnson syndrome mutation impairs protein maturation and transport activity of MRP2(ABCC2). Am J Physiol Gastrointest Liver Physiol. 2003;284:G165-174. https://doi.org/10.1152/ajpgi.00362.2002
  40. Jamroziak K, Balcerczak E, Smolewski P, Robey RW, Cebula B, Panczyk M, Kowalczyk M, Szmigielska-Kap on A, Mirowski M, Bates SE, Robak T. MDR1 (ABCB1) gene polymorphism C3435T is associated with P-glycoprotein activity in B-cell chronic lymphocytic leukemia. Pharmacol Rep. 2006;58:720-728.
  41. Ogasawara K, Terada T, Motohashi H, Asaka J, Aoki M, Katsura T, Kamba T, Ogawa O, Inui K. Analysis of regulatory polymorphisms in organic ion transporter genes (SLC22A) in the kidney. J Hum Genet. 2008;53:607-614. https://doi.org/10.1007/s10038-008-0288-9

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