메뉴 건너뛰기




Volumn 610, Issue 1-2, 2006, Pages 114-123

Molecular analysis of hprt mutations induced by chromium picolinate in CHO AA8 cells

Author keywords

Chinese hamster ovary; Chromium picolinate; Genotoxicity; hprt; Mutational spectrum

Indexed keywords

ACETONE; CHROMIUM PICOLINATE; DIMETHYL SULFOXIDE; HYPOXANTHINE PHOSPHORIBOSYLTRANSFERASE; SOLVENT; TIOGUANINE;

EID: 33749250186     PISSN: 13835718     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.mrgentox.2006.06.020     Document Type: Article
Times cited : (45)

References (52)
  • 1
    • 33749257950 scopus 로고    scopus 로고
    • H. Boynton, G.W. Evans, Chromium picolinate treatment, US Patent 5,087,624 (1992).
  • 2
    • 84990976585 scopus 로고    scopus 로고
    • Controversial chromium: does the superstar mineral of the mountebanks receive appropriate attention from clinicians and nutritionists?
    • Nielsen F.H. Controversial chromium: does the superstar mineral of the mountebanks receive appropriate attention from clinicians and nutritionists?. Nutr. Today 31 (1996) 226-233
    • (1996) Nutr. Today , vol.31 , pp. 226-233
    • Nielsen, F.H.1
  • 3
    • 0008410042 scopus 로고    scopus 로고
    • Chromium picolinate market sees robust growth and high demand
    • Mirasol F. Chromium picolinate market sees robust growth and high demand. Chem. Market Rep. 257 (2000) 26
    • (2000) Chem. Market Rep. , vol.257 , pp. 26
    • Mirasol, F.1
  • 4
    • 0013112431 scopus 로고    scopus 로고
    • Chromium picolinate for reducing body weight: meta-analysis of randomized trials
    • Pittler M.H., Stevinson C., and Ernst E. Chromium picolinate for reducing body weight: meta-analysis of randomized trials. Int. J. Obes. 27 (2003) 522-529
    • (2003) Int. J. Obes. , vol.27 , pp. 522-529
    • Pittler, M.H.1    Stevinson, C.2    Ernst, E.3
  • 5
    • 0027026642 scopus 로고
    • Effects of chromium picolinate on beginning weight training students
    • Hasten D.L., Rome E.P., Franks B.D., and Hegsted M. Effects of chromium picolinate on beginning weight training students. Int. J. Sport Nutr. 2 (1992) 343-350
    • (1992) Int. J. Sport Nutr. , vol.2 , pp. 343-350
    • Hasten, D.L.1    Rome, E.P.2    Franks, B.D.3    Hegsted, M.4
  • 7
    • 0029834894 scopus 로고    scopus 로고
    • Effects of chromium picolinate supplementation on body composition: a randomized, double-masked, placebo-controlled study
    • Kaats G.R., Blum K., Fisher J.A., and Adelman J.A. Effects of chromium picolinate supplementation on body composition: a randomized, double-masked, placebo-controlled study. Curr. Ther. Res. 57 (1996) 747-756
    • (1996) Curr. Ther. Res. , vol.57 , pp. 747-756
    • Kaats, G.R.1    Blum, K.2    Fisher, J.A.3    Adelman, J.A.4
  • 9
    • 0031866814 scopus 로고    scopus 로고
    • Randomized, double-masked, placebo-controlled study of the effects of chromium picolinate supplementation on body composition: a replication and extension of a previous study
    • Kaats G.R., Blum K., Pullin D., Keith S.C., and Wood R.A. Randomized, double-masked, placebo-controlled study of the effects of chromium picolinate supplementation on body composition: a replication and extension of a previous study. Curr. Ther. Res. 59 (1998) 379-388
    • (1998) Curr. Ther. Res. , vol.59 , pp. 379-388
    • Kaats, G.R.1    Blum, K.2    Pullin, D.3    Keith, S.C.4    Wood, R.A.5
  • 10
    • 0032434265 scopus 로고    scopus 로고
    • Chromium picolinate effects on body composition and muscular performance in wrestlers
    • Walker L.S., Bemben M.G., Bemben D.A., and Knehans A.W. Chromium picolinate effects on body composition and muscular performance in wrestlers. Med. Sci. Sports Exerc. 30 (1998) 1730-1737
    • (1998) Med. Sci. Sports Exerc. , vol.30 , pp. 1730-1737
    • Walker, L.S.1    Bemben, M.G.2    Bemben, D.A.3    Knehans, A.W.4
  • 11
    • 0032961368 scopus 로고    scopus 로고
    • Effects of resistance training and chromium picolinate on body composition and skeletal muscle in older men
    • Campbell W.W., Joseph L.J., Davey S.L., Cyr-Campbell D., Anderson R.A., and Evans W.J. Effects of resistance training and chromium picolinate on body composition and skeletal muscle in older men. J. Appl. Physiol. 86 (1999) 29-39
    • (1999) J. Appl. Physiol. , vol.86 , pp. 29-39
    • Campbell, W.W.1    Joseph, L.J.2    Davey, S.L.3    Cyr-Campbell, D.4    Anderson, R.A.5    Evans, W.J.6
  • 12
    • 0032897624 scopus 로고    scopus 로고
    • Effect of resistance training with or without chromium picolinate supplementation on glucose metabolism in older men and women
    • Joseph L.J.O., Farrel P.A., Davey S.L., Evans W.J., and Campbell W.W. Effect of resistance training with or without chromium picolinate supplementation on glucose metabolism in older men and women. Metabolism 48 (1999) 546-553
    • (1999) Metabolism , vol.48 , pp. 546-553
    • Joseph, L.J.O.1    Farrel, P.A.2    Davey, S.L.3    Evans, W.J.4    Campbell, W.W.5
  • 13
    • 0035346572 scopus 로고    scopus 로고
    • The effect of chromium picolinate on muscular strength and body composition in women athletes
    • Livolsi J.M., Adams G.M., and Laguna P.L. The effect of chromium picolinate on muscular strength and body composition in women athletes. J. Strength Cond. Res. 15 (2001) 161-166
    • (2001) J. Strength Cond. Res. , vol.15 , pp. 161-166
    • Livolsi, J.M.1    Adams, G.M.2    Laguna, P.L.3
  • 14
    • 0034879741 scopus 로고    scopus 로고
    • Effect of chromium supplementation and exercise on body composition, resting metabolic rate and selected biochemical parameters in moderately obese women following an exercise program
    • Volpe S.L., Huang H.W., Larpadisorn K., and Lesser I.I. Effect of chromium supplementation and exercise on body composition, resting metabolic rate and selected biochemical parameters in moderately obese women following an exercise program. J. Am. Coll. Nutr. 20 (2001) 293-306
    • (2001) J. Am. Coll. Nutr. , vol.20 , pp. 293-306
    • Volpe, S.L.1    Huang, H.W.2    Larpadisorn, K.3    Lesser, I.I.4
  • 15
    • 0027949040 scopus 로고
    • Beneficial effect of chromium supplementation on serum triglyceride levels in NIDDM
    • Lee N.A., and Reasner C.A. Beneficial effect of chromium supplementation on serum triglyceride levels in NIDDM. Diab. Care 17 (1994) 1449-1452
    • (1994) Diab. Care , vol.17 , pp. 1449-1452
    • Lee, N.A.1    Reasner, C.A.2
  • 16
    • 0032708471 scopus 로고    scopus 로고
    • Reversal of corticosteroid-induced diabetes mellitus with supplemental chromium
    • Ravina A., Slezak L., Mirsky N., Bryden N.A., and Anderson R.A. Reversal of corticosteroid-induced diabetes mellitus with supplemental chromium. Diab. Med. 16 (1999) 164-167
    • (1999) Diab. Med. , vol.16 , pp. 164-167
    • Ravina, A.1    Slezak, L.2    Mirsky, N.3    Bryden, N.A.4    Anderson, R.A.5
  • 17
    • 0030695031 scopus 로고    scopus 로고
    • Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes
    • Anderson R.A., Cheng N., Bryden N.A., Polansky M.M., Cheng N., Chi J., and Feng J. Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes 46 (1997) 1786-1791
    • (1997) Diabetes , vol.46 , pp. 1786-1791
    • Anderson, R.A.1    Cheng, N.2    Bryden, N.A.3    Polansky, M.M.4    Cheng, N.5    Chi, J.6    Feng, J.7
  • 19
    • 0021881034 scopus 로고
    • Chromium intake, absorption and excretion of subjects consuming self-selected diets
    • Anderson R.A., and Kozlovsky A.S. Chromium intake, absorption and excretion of subjects consuming self-selected diets. Am. J. Clin. Nutr. 41 (1985) 1177-1183
    • (1985) Am. J. Clin. Nutr. , vol.41 , pp. 1177-1183
    • Anderson, R.A.1    Kozlovsky, A.S.2
  • 21
    • 33749266998 scopus 로고    scopus 로고
    • M. McCarty, High-dose chromic picolinate treatment of type II diabetes, US Patent 6,329,361 (2001).
  • 22
    • 0029592799 scopus 로고
    • A prediction of chromium(III) accumulation in humans from chromium dietary supplements
    • Stearns D.M., BelBruno J.J., and Wetterhahn K.E. A prediction of chromium(III) accumulation in humans from chromium dietary supplements. FASEB J. 9 (1995) 1650-1657
    • (1995) FASEB J. , vol.9 , pp. 1650-1657
    • Stearns, D.M.1    BelBruno, J.J.2    Wetterhahn, K.E.3
  • 23
    • 0030023466 scopus 로고    scopus 로고
    • Transperitoneal absorption and kinetics of chromium in the continuous ambulatory peritoneal dialysis patient-an experimental and mathematical analysis
    • Borguet F., Wallaeys B., Cornelis R., and Lameire N. Transperitoneal absorption and kinetics of chromium in the continuous ambulatory peritoneal dialysis patient-an experimental and mathematical analysis. Nephron 72 (1996) 163-170
    • (1996) Nephron , vol.72 , pp. 163-170
    • Borguet, F.1    Wallaeys, B.2    Cornelis, R.3    Lameire, N.4
  • 25
    • 0029603641 scopus 로고
    • Chromium(III) picolinate produces chromosome damage in Chinese hamster ovary cells
    • Stearns D.M., Wise Sr. J.P., Patierno S.R., and Wetterhahn K.E. Chromium(III) picolinate produces chromosome damage in Chinese hamster ovary cells. FASEB J. 9 (1995) 1643-1648
    • (1995) FASEB J. , vol.9 , pp. 1643-1648
    • Stearns, D.M.1    Wise Sr., J.P.2    Patierno, S.R.3    Wetterhahn, K.E.4
  • 26
    • 0035863782 scopus 로고    scopus 로고
    • Chromium(III) tris(picolinate) is mutagenic at the hypoxanthine (guanine) phosphoribosyltransferase locus in Chinese hamster ovary cells
    • Stearns D.M., Silveira S.M., Wolf K.K., and Luke A.M. Chromium(III) tris(picolinate) is mutagenic at the hypoxanthine (guanine) phosphoribosyltransferase locus in Chinese hamster ovary cells. Mutat. Res. 513 (2002) 135-142
    • (2002) Mutat. Res. , vol.513 , pp. 135-142
    • Stearns, D.M.1    Silveira, S.M.2    Wolf, K.K.3    Luke, A.M.4
  • 27
    • 0036940895 scopus 로고    scopus 로고
    • Ultrastructural damage in chromium picolinate-treated cells: a TEM study
    • Manygoats K.R., Yazzie M., and Stearns D.M. Ultrastructural damage in chromium picolinate-treated cells: a TEM study. J. Inorg. Biochem. 7 (2002) 791-798
    • (2002) J. Inorg. Biochem. , vol.7 , pp. 791-798
    • Manygoats, K.R.1    Yazzie, M.2    Stearns, D.M.3
  • 28
    • 22144456401 scopus 로고    scopus 로고
    • Lack of mutagenicity of chromium picolinate in the hypoxanthine phosphoribosyltransferase gene mutation assay in Chinese hamster ovary cells
    • Slesinski R.S., Clarke J.J., San R.H.C., and Gudi R. Lack of mutagenicity of chromium picolinate in the hypoxanthine phosphoribosyltransferase gene mutation assay in Chinese hamster ovary cells. Mutat. Res. 585 (2005) 86-95
    • (2005) Mutat. Res. , vol.585 , pp. 86-95
    • Slesinski, R.S.1    Clarke, J.J.2    San, R.H.C.3    Gudi, R.4
  • 29
    • 27144556601 scopus 로고    scopus 로고
    • Chromium picolinate does not produce chromosome damage in CHO cells
    • Gudi R., Slesinski R.S., Clarke J.J., and San R.H. Chromium picolinate does not produce chromosome damage in CHO cells. Mutat. Res. 587 (2005) 140-146
    • (2005) Mutat. Res. , vol.587 , pp. 140-146
    • Gudi, R.1    Slesinski, R.S.2    Clarke, J.J.3    San, R.H.4
  • 30
    • 0037386661 scopus 로고    scopus 로고
    • Nutritional supplement chromium picolinate causes sterility and lethal mutations in Drosophila melanogaster
    • Hepburn D.D.D., Xiao J., Bindom S., Vincent J.B., and O'Donnell J. Nutritional supplement chromium picolinate causes sterility and lethal mutations in Drosophila melanogaster. Proc. Natl. Acad. Sci. U.S.A. 100 (2003) 3766-3771
    • (2003) Proc. Natl. Acad. Sci. U.S.A. , vol.100 , pp. 3766-3771
    • Hepburn, D.D.D.1    Xiao, J.2    Bindom, S.3    Vincent, J.B.4    O'Donnell, J.5
  • 31
    • 24644443253 scopus 로고    scopus 로고
    • Mutagenicity of chromium picolinate and its components in Salmonella typhimurium and L5178Y mouse lymphoma cells
    • Whittaker P., San R.H., Clarke J.J., Seifried H.E., and Dunkel V.C. Mutagenicity of chromium picolinate and its components in Salmonella typhimurium and L5178Y mouse lymphoma cells. Food Chem. Toxicol. 43 (2005) 1619-1625
    • (2005) Food Chem. Toxicol. , vol.43 , pp. 1619-1625
    • Whittaker, P.1    San, R.H.2    Clarke, J.J.3    Seifried, H.E.4    Dunkel, V.C.5
  • 32
    • 0028790076 scopus 로고
    • Molecular nature of spontaneous mutations at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus in Chinese hamster ovary cells
    • Xu Z., Yu Y., Schwartz J.L., Meltz M.L., and Hsie A.W. Molecular nature of spontaneous mutations at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus in Chinese hamster ovary cells. Environ. Mol. Mutagen. 26 (1995) 127-138
    • (1995) Environ. Mol. Mutagen. , vol.26 , pp. 127-138
    • Xu, Z.1    Yu, Y.2    Schwartz, J.L.3    Meltz, M.L.4    Hsie, A.W.5
  • 33
    • 31044455224 scopus 로고    scopus 로고
    • Molecular analysis of hprt mutations generated in Chinese hamster ovary EM9 cells by uranyl acetate, by hydrogen peroxide, and spontaneously
    • Coryell V.H., and Stearns D.M. Molecular analysis of hprt mutations generated in Chinese hamster ovary EM9 cells by uranyl acetate, by hydrogen peroxide, and spontaneously. Mol. Carcinog. 45 (2006) 60-72
    • (2006) Mol. Carcinog. , vol.45 , pp. 60-72
    • Coryell, V.H.1    Stearns, D.M.2
  • 34
    • 0004252445 scopus 로고
    • Prentice-Hall, Inc., Englewood Cliffs, NJ pp. 52-53
    • Zar J.H. Biostatistical Analysis. 2nd ed. (1984), Prentice-Hall, Inc., Englewood Cliffs, NJ pp. 52-53
    • (1984) Biostatistical Analysis. 2nd ed.
    • Zar, J.H.1
  • 36
    • 0032212402 scopus 로고    scopus 로고
    • Mutations that alter RNA splicing of the human HPRT gene: a review of the spectrum
    • O'Neill J.P., Rogan P.K., Cariello N., and Nicklas J.A. Mutations that alter RNA splicing of the human HPRT gene: a review of the spectrum. Mutat. Res. 411 (1998) 179-214
    • (1998) Mutat. Res. , vol.411 , pp. 179-214
    • O'Neill, J.P.1    Rogan, P.K.2    Cariello, N.3    Nicklas, J.A.4
  • 37
    • 0017081747 scopus 로고
    • The uptake and retention of chromium by cells
    • Sanderson C.J. The uptake and retention of chromium by cells. Transplantation 21 (1976) 526-529
    • (1976) Transplantation , vol.21 , pp. 526-529
    • Sanderson, C.J.1
  • 38
    • 0028673929 scopus 로고
    • Dimethyl sulphoxide: a review of its applications in cell biology
    • Yu Z.W., and Quinn P.J. Dimethyl sulphoxide: a review of its applications in cell biology. Biosci. Rep. 14 (1994) 259-281
    • (1994) Biosci. Rep. , vol.14 , pp. 259-281
    • Yu, Z.W.1    Quinn, P.J.2
  • 39
    • 0030684752 scopus 로고    scopus 로고
    • Comparative induction of oxidative stress in cultured J774A.1 macrophage cells by chromium picolinate and chromium nicotinate
    • Bagchi D., Bagchi M., Balmoori J., Ye X., and Stohs S.J. Comparative induction of oxidative stress in cultured J774A.1 macrophage cells by chromium picolinate and chromium nicotinate. Res. Commun. Mol. Pathol. Pharmacol. 97 (1997) 335-346
    • (1997) Res. Commun. Mol. Pathol. Pharmacol. , vol.97 , pp. 335-346
    • Bagchi, D.1    Bagchi, M.2    Balmoori, J.3    Ye, X.4    Stohs, S.J.5
  • 40
    • 0037201935 scopus 로고    scopus 로고
    • Cytotoxicity and oxidative mechanisms of different forms of chromium
    • Bagchi D., Stohs S.J., Downs B.W., Bagchi M., and Preuss H.G. Cytotoxicity and oxidative mechanisms of different forms of chromium. Toxicology 180 (2002) 5-22
    • (2002) Toxicology , vol.180 , pp. 5-22
    • Bagchi, D.1    Stohs, S.J.2    Downs, B.W.3    Bagchi, M.4    Preuss, H.G.5
  • 41
    • 0037322256 scopus 로고    scopus 로고
    • The nutritional supplement chromium picolinate generated oxidative DNA damage and peroxidized lipids in vivo
    • Hepburn D.D.D., Burney J.M., Woski S.A., and Vincent J.B. The nutritional supplement chromium picolinate generated oxidative DNA damage and peroxidized lipids in vivo. Polyhedron 22 (2003) 455-463
    • (2003) Polyhedron , vol.22 , pp. 455-463
    • Hepburn, D.D.D.1    Burney, J.M.2    Woski, S.A.3    Vincent, J.B.4
  • 44
    • 0028927261 scopus 로고
    • Reactions of oxyl radicals with DNA
    • Breen A.P., and Murphy J.A. Reactions of oxyl radicals with DNA. Free Radic. Biol. Med. 18 (1995) 1033-1077
    • (1995) Free Radic. Biol. Med. , vol.18 , pp. 1033-1077
    • Breen, A.P.1    Murphy, J.A.2
  • 45
    • 0025981359 scopus 로고
    • Insertion of specific bases during DNA synthesis past the oxidation damage base 8-oxodG
    • Shibutani S., Takeshita M., and Grollman A.P. Insertion of specific bases during DNA synthesis past the oxidation damage base 8-oxodG. Nature 349 (1991) 431-434
    • (1991) Nature , vol.349 , pp. 431-434
    • Shibutani, S.1    Takeshita, M.2    Grollman, A.P.3
  • 46
    • 0033555373 scopus 로고    scopus 로고
    • Insertion of dGMP and dAMP during in vitro DNA synthesis opposite an oxidized form of 7,8-dihydro-8-oxoguanine
    • Duart V., Muller J.G., and Burrows C.J. Insertion of dGMP and dAMP during in vitro DNA synthesis opposite an oxidized form of 7,8-dihydro-8-oxoguanine. Nucl. Acids Res. 27 (1999) 496-502
    • (1999) Nucl. Acids Res. , vol.27 , pp. 496-502
    • Duart, V.1    Muller, J.G.2    Burrows, C.J.3
  • 47
    • 0034814369 scopus 로고    scopus 로고
    • Direct oxidation of guanine and 7,8-dihydro-8-oxoguanine in DNA by a high-valent chromium complex: a possible mechanism for chromate genotoxicity
    • Sugden K.D., Campo C.K., and Martin B.D. Direct oxidation of guanine and 7,8-dihydro-8-oxoguanine in DNA by a high-valent chromium complex: a possible mechanism for chromate genotoxicity. Chem. Res. Toxicol. 14 (2001) 1315-1322
    • (2001) Chem. Res. Toxicol. , vol.14 , pp. 1315-1322
    • Sugden, K.D.1    Campo, C.K.2    Martin, B.D.3
  • 48
    • 0037154121 scopus 로고    scopus 로고
    • Oxidation of 7,8-dihydro-8-oxoguanine affords lesions that are potent sources of replication errors in vivo
    • Henderson P.T., Delaney J.C., Gu F., Tannenbaum S.R., and Essigmann J.M. Oxidation of 7,8-dihydro-8-oxoguanine affords lesions that are potent sources of replication errors in vivo. Biochemistry 41 (2002) 914-921
    • (2002) Biochemistry , vol.41 , pp. 914-921
    • Henderson, P.T.1    Delaney, J.C.2    Gu, F.3    Tannenbaum, S.R.4    Essigmann, J.M.5
  • 49
    • 0037168491 scopus 로고    scopus 로고
    • In vitro nucleotide misinsertion opposite the oxidized guanosine lesions spiroiminodihydantoin and guanidinohydantoin and DNA synthesis past the lesions using Escherichia coli DNA polymerase I (Klenow fragment)
    • Kornyushyna O., Berges A.M., Muller J.G., and Burrows C.J. In vitro nucleotide misinsertion opposite the oxidized guanosine lesions spiroiminodihydantoin and guanidinohydantoin and DNA synthesis past the lesions using Escherichia coli DNA polymerase I (Klenow fragment). Biochemistry 41 (2002) 15304-15314
    • (2002) Biochemistry , vol.41 , pp. 15304-15314
    • Kornyushyna, O.1    Berges, A.M.2    Muller, J.G.3    Burrows, C.J.4
  • 50
    • 0041571565 scopus 로고    scopus 로고
    • The hydantoin lesions formed from oxidation of 7,8-dihydro-8-oxoguanine are potent sources of replication errors in vivo
    • Henderson P.T., Delaney J.C., Muller J.G., Neeley W.L., Tannenbaum S.R., Burrows C.J., and Essigmann J.M. The hydantoin lesions formed from oxidation of 7,8-dihydro-8-oxoguanine are potent sources of replication errors in vivo. Biochemistry 42 (2003) 9257-9262
    • (2003) Biochemistry , vol.42 , pp. 9257-9262
    • Henderson, P.T.1    Delaney, J.C.2    Muller, J.G.3    Neeley, W.L.4    Tannenbaum, S.R.5    Burrows, C.J.6    Essigmann, J.M.7
  • 51
    • 0027423164 scopus 로고
    • Molecular analysis of mutations at the tk locus of L5178Y mouse-lymphoma cells induced by ethyl methanesulphonate and mitomycin C
    • Davies M.J., Phillips B.J., and Rumsby P.C. Molecular analysis of mutations at the tk locus of L5178Y mouse-lymphoma cells induced by ethyl methanesulphonate and mitomycin C. Mutat. Res. 290 (1993) 145-153
    • (1993) Mutat. Res. , vol.290 , pp. 145-153
    • Davies, M.J.1    Phillips, B.J.2    Rumsby, P.C.3
  • 52
    • 0031796958 scopus 로고    scopus 로고
    • PCR-directed DNA sequencing of "nondeletion" HPRT-mutants induced by bleomycin in CHO K1-BH4 cells
    • An J., Trieff N.M., and Hsie A.W. PCR-directed DNA sequencing of "nondeletion" HPRT-mutants induced by bleomycin in CHO K1-BH4 cells. Environ. Mol. Mutagen. 32 (1998) 244-250
    • (1998) Environ. Mol. Mutagen. , vol.32 , pp. 244-250
    • An, J.1    Trieff, N.M.2    Hsie, A.W.3


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.