Abstract
Most people generally ingest cadmium in their food. Cadmium that has accumulated in tissues induces the synthesis of metallothioneins (MTs) which are metal-binding proteins that bind tightly to cadmium to inhibit its renal toxicity. Individuals whose ability to induce the synthesis of MTs is low seem likely to be particularly susceptible to the toxic effects of cadmium. In this study, we analyzed the polymorphism of the promoter region of the gene for MT-IIA, the major species of MT in humans, in 119 adult Japanese subjects. We found that about 18% of the subjects had an A → G single-nucleotide polymorphism in the core region of the promoter near the TATA box. A reporter-gene assay using HEK293 cells showed that replacement of A by G at position −5 reduced the efficiency of the cadmium-induced transcription of the gene for MT-IIA. This single-nucleotide polymorphism inhibited the binding of nuclear proteins to the core promoter region of the gene for MT-IIA. When the promoter region upstream of the TATA box was replaced by a sequence that contained three dioxin-responsive elements, the reporter-gene assay demonstrated that the A → G single-nucleotide polymorphism resulted in a marked reduction in the rate of dioxin-induced transcription. These results suggest that the A → G single-nucleotide polymorphism reduces the efficiency of those aspects of the transcription of the gene for MT-IIA that are controlled by general transcription factors.
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References
Cagen SZ, Klaassen CD (1979) Protection of carbon tetrachloride-induced hepatotoxicity by zinc: role of metallothionein. Toxicol Appl Pharmacol 51:107–16
Carter AD, Felber BK, Walling MJ, Jubier MF, Schmidt CJ, Hamer DH (1984) Duplicated heavy metal control sequences of the mouse metallothionein-I gene. Proc Natl Acad Sci USA 81:7392–7396
Chalkley GE, Verrijzer CP (1999) DNA binding site selection by RNA polymerase II TAFs: a TAF(II)250–TAF(II)150 complex recognizes the initiator. EMBO J 18:4835–4845
Friberg L, Vahter M (1983) Assessment of exposure to lead and cadmium through biological monitoring: results of a UNEP/WHO global study. Environ Res 30:95–128
Johnson MD, Kenney N, Stoica A, Hilakivi-Clarke L, Singh B, Chepko G, Clarke R, Sholler PF, Lirio AA, Foss C, Reiter R, Trock B, Paik S, Martin MB (2003) Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland. Nat Med 9:1081–4
Kägi JHR (1991) Overview of metallothionein. Methods Enzymol 205:613–626
Karin M, Haslinger A, Holtgreve H, Krauter P, Westphal M, Beato M (1984) Characterization of DNA sequences through which cadmium and glucocorticoid hormones induce human metallothionein-IIA gene. Nature 308:513–519
Kita K, Miura N, Yoshida M, Matsubara K, Imai Y, Naganuma A (2001) Original MRE-binding transcriptional factor gene in normal humans is ZRF, not MTF-1. J Health Sci 47:587–590
Koizumi S, Suzuki K, Ogra Y, Yamada H, Otsuka F (1999) Transcriptional activity and regulatory protein binding of metal-responsive elements of the human metallothionein-IIA gene. Eur J Biochem 259:635–642
Liu Y, Liu J, Habeebu SM, Waalkes MP, Klaassen CD (2000) Metallothionein-I/II null mice are sensitive to chronic oral cadmium-induced nephrotoxicity. Toxicol Sci 57:167–76
Muller MM, Schreiber E, Schaffner W, Matthias P (1989) Rapid test for in vivo stability and DNA binding of mutated octamer binding proteins with ‘mini-extracts’ prepared from transfected cells. Nucleic Acids Res 17:6420
Naganuma A, Satoh M, Imura N (1987) Prevention of lethal and renal toxicity of cis-diamminedichloroplatinum(II) by induction of metallothionein synthesis without compromising its antitumor activity in mice. Cancer Res 47:983–987
Naganuma A, Satoh M, Imura N (1988) Specific reduction of toxic side effects of adriamycin by induction of metallothionein in mice. Jpn J Cancer Res 79:406–411
Okazaki Y, Miura N, Satoh M, Imura N, Naganuma A (1998) Metallothionein-mediated resistance to multiple drugs can be induced by several anticancer drugs in mice. Biochem Biophys Res Commun 245:815–818
Olsson IM, Bensryd I, Lundh T, Ottosson H, Skerfving S, Oskarsson A (2002) Cadmium in blood and urine—impact of sex, age, dietary intake, iron status, and former smoking—association of renal effects. Environ Health Perspect 110:1185–90
Otsuka F, Iwamatsu A, Suzuki K, Ohsawa M, Hamer DH, Koizumi S (1994) Purification and characterization of a protein that binds to metal responsive elements of the human metallothionein IIA gene. J Biol Chem 269:23700–23707
Robert F, Forget D, Li J, Greenblatt J, Coulombe B (1996) Localization of subunits of transcription factors IIE and IIF immediately upstream of the transcriptional initiation site of the adenovirus major late promoter. J Biol Chem 271:8517–8520
Saito H, Shioji T, Furukawa T, Nagai K, Arikawa T, Saito T, Sasaki Y, Furuyama T, Yoshinaga K (1977) Cadmium-induced proximal tubular dysfunction in a cadmium-polluted area. Contrib Nephrol 6:1–12
Sato M, Bremner I (1993) Oxygen free radicals and metallothionein. Free Radic Biol Med 14:325–337
Satoh M, Miura N, Naganuma A, Matsuzaki N, Kawamura E, Imura N (1989) Prevention of adverse effects of g-ray irradiation by metallothionein induction by bismuth subnitrate in mice. Eur J Cancer Clin Oncol 25:1727–1731
Satoh M, Naganuma A, Imura N (1992) Effect of preinduction of metallothionein on paraquat toxicity in mice. Arch Toxicol 66:145–148
Satoh M, Kondo Y, Mita M, Nakagawa I, Naganuma A, Imura N (1993a) Prevention of carcinogenicity of anticancer drugs by metallothionein induction. Cancer Res 53:4767–4768
Satoh M, Tsuchiya T, Kumada Y, Naganuma A, Imura N (1993b) Protection against lethal toxicity of various anticancer drugs by preinduction of metallothionein synthesis in mice. J Trace Elem Exp Med 6:41–44
Stuart GW, Searle PF, Palmiter RD (1985) Identification of multiple metal regulatory elements in mouse metallothionein-I promoter by assaying synthetic sequences. Nature 317:828–831
Webb M (1979) The chemistry, biochemistry and biology of cadmium. Elsevier/North-Holland, Amsterdam
Westin G, Schaffner W (1988) A zinc-responsive factor interacts with a metal-regulated enhancer element (MRE) of the mouse metallothionein-I gene. EMBO J 7:3763–3770
WHO (1993) Cadmium. World Health Organization, Geneva
Yanai K, Saito T, Hirota K, Kobayashi H, Murakami K, Fukamizu A (1997) Molecular variation of the human angiotensinogen core promoter element located between the TATA box and transcription initiation site affects its transcriptional activity. J Biol Chem 272:30558–30562
Yean D, Gralla J (1997) Transcription reinitiation rate: a special role for the TATA box. Mol Cell Biol 17:3809–3816
Yoshida M, Ohta H, Yamauchi Y, Seki Y, Sagi M, Yamazaki K, Sumi Y (1998) Age-dependent changes in metallothionein levels in liver and kidney of the Japanese. Biol Trace Elem Res 63:167–175
Zhang B, Satoh M, Nishimura N, Suzuki JS, Sone H, Aoki Y, Tohyama C (1998) Metallothionein deficiency promotes mouse skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene. Cancer Res 58:4044–4046
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This work was supported by a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science and by Health and Labour Sciences Research Grants for Research on the Risk of Chemical Substances from the Ministry of Health, Labour and Welfare, Japan.
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Kita, K., Miura, N., Yoshida, M. et al. Potential effect on cellular response to cadmium of a single-nucleotide A → G polymorphism in the promoter of the human gene for metallothionein IIA. Hum Genet 120, 553–560 (2006). https://doi.org/10.1007/s00439-006-0238-6
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DOI: https://doi.org/10.1007/s00439-006-0238-6