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Volumn 78, Issue 4, 1996, Pages 241-248

The involvement of cytochrome P4502E1 in 2-bromoethanol-induced hepatocyte cytotoxicity

Author keywords

[No Author keywords available]

Indexed keywords

2 BROMOACETALDEHYDE; 2 BROMOETHANOL; ALCOHOL; ALCOHOL DERIVATIVE; ALDEHYDE DERIVATIVE; ALLYL ALCOHOL; BROMOACETIC ACID; BUTYLATED HYDROXYANISOLE; CARBON DISULFIDE; CHLORAL HYDRATE; CYANAMIDE; CYTOCHROME P450 ISOENZYME; DEFEROXAMINE; DIMETHYL SULFOXIDE; GLUTATHIONE; IMIDAZOLE DERIVATIVE; ISONIAZID; PHENYLENEDIAMINE DERIVATIVE; PROADIFEN; PYRAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

EID: 0029929547     PISSN: 09019928     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1600-0773.1996.tb00212.x     Document Type: Article
Times cited : (7)

References (53)
  • 2
    • 9244262445 scopus 로고
    • Sigma-Aldrich Corp. Milwaukee, WI
    • Aldrich Chemical Co: 2-Bromoethanol-Material safety data sheet. Sigma-Aldrich Corp. Milwaukee, WI, 1990, 3 pages.
    • (1990) 2-Bromoethanol-Material Safety Data Sheet , pp. 3
  • 3
  • 4
    • 0018642315 scopus 로고
    • Interaction of potential metabolites of the carcinogen ethylene dibromide with protein and DNA in vitro
    • Banerjee, S., B. L. Van Duuren & S. A. Kline: Interaction of potential metabolites of the carcinogen ethylene dibromide with protein and DNA in vitro. Biochem. Biophys. Res. Commun. 1979, 90, 1214-1220.
    • (1979) Biochem. Biophys. Res. Commun. , vol.90 , pp. 1214-1220
    • Banerjee, S.1    Van Duuren, B.L.2    Kline, S.A.3
  • 5
    • 0020551014 scopus 로고
    • Evidence for binding of metabolically activated 1,2-bromoethane to chromatin of forestomach and liver
    • Banerjee, S. & B. L. Van Duuren: Evidence for binding of metabolically activated 1,2-bromoethane to chromatin of forestomach and liver. Life Sci. 1983, 33, 1763-1770.
    • (1983) Life Sci. , vol.33 , pp. 1763-1770
    • Banerjee, S.1    Van Duuren, B.L.2
  • 7
    • 0017158099 scopus 로고
    • SKF 525-A inhibition, induction and 452 nm complex formation
    • Buening, M. K. & M. R. Franklin: SKF 525-A inhibition, induction and 452 nm complex formation. Drug Metab. Disp. 1976, 4, 244-255.
    • (1976) Drug Metab. Disp. , vol.4 , pp. 244-255
    • Buening, M.K.1    Franklin, M.R.2
  • 8
    • 0019868268 scopus 로고
    • The effect of cyanamide on the metabolism of ethanol and acetaldehyde and on gluconeogenesis by isolated rat hepatocytes
    • Cederbaum, A. I. & E. Dicker: The effect of cyanamide on the metabolism of ethanol and acetaldehyde and on gluconeogenesis by isolated rat hepatocytes. Biochem. Pharmacol. 1981, 30, 3079-3098.
    • (1981) Biochem. Pharmacol. , vol.30 , pp. 3079-3098
    • Cederbaum, A.I.1    Dicker, E.2
  • 9
    • 0025328845 scopus 로고
    • Comparison of the interaction of pyrazole and its metabolite 4-hydroxypyrazole with rat liver microsomes
    • Clejan, L. A. & A. I. Cederbaum: Comparison of the interaction of pyrazole and its metabolite 4-hydroxypyrazole with rat liver microsomes. Drug Metab. Disp. 1990, 18, 393-397.
    • (1990) Drug Metab. Disp. , vol.18 , pp. 393-397
    • Clejan, L.A.1    Cederbaum, A.I.2
  • 10
    • 0020858858 scopus 로고
    • The inhibition of alcohol dehydrogenase in vitro and in isolated hepatocytes by 4-substituted pyrazoles
    • Cornell, N. W, C. Haansch, K. H. Kim & K. Henegar: The inhibition of alcohol dehydrogenase in vitro and in isolated hepatocytes by 4-substituted pyrazoles. Arch. Biochem. Biophys. 1983, 227, 81-90.
    • (1983) Arch. Biochem. Biophys. , vol.227 , pp. 81-90
    • Cornell, N.W.1    Haansch, C.2    Kim, K.H.3    Henegar, K.4
  • 11
    • 0019286784 scopus 로고
    • Changes in mitochondria respiration and red blood cell morphology due to 2-halogeno-ethanols
    • Ebina, S., S. I. Nakai & Y. Nagai: Changes in mitochondria respiration and red blood cell morphology due to 2-halogeno-ethanols. Fukushima J. Med. Sci. 1980, 27, 11-24.
    • (1980) Fukushima J. Med. Sci. , vol.27 , pp. 11-24
    • Ebina, S.1    Nakai, S.I.2    Nagai, Y.3
  • 12
    • 84988106922 scopus 로고
    • Enzyme-structure relationships in the endoplasmic reticulum on the rat liver: A morphological and biochemical study
    • Ernster, L., P. Siekevitz & G. E. Palade: Enzyme-structure relationships in the endoplasmic reticulum on the rat liver: a morphological and biochemical study. J. Cell Biol. 1962, 15, 541-562.
    • (1962) J. Cell Biol. , vol.15 , pp. 541-562
    • Ernster, L.1    Siekevitz, P.2    Palade, G.E.3
  • 13
    • 0022852729 scopus 로고
    • Inhibition of microsomal oxidation of ethanol by pyrazole and 4-methylpyrazole in vitro. Increased sensitivity after induction by pyrazole and 4-methylpyrazole
    • Feierman, D. E. & A. I. Cederbaum: Inhibition of microsomal oxidation of ethanol by pyrazole and 4-methylpyrazole in vitro. Increased sensitivity after induction by pyrazole and 4-methylpyrazole. Biochem. J. 1986, 239, 671-677.
    • (1986) Biochem. J. , vol.239 , pp. 671-677
    • Feierman, D.E.1    Cederbaum, A.I.2
  • 14
    • 0023552690 scopus 로고
    • Halogenated compounds as inducers of lipid peroxidation in tissue slices
    • Fraga, C. G., B. E. Leibovitz & A. K. Tappel: Halogenated compounds as inducers of lipid peroxidation in tissue slices. Free Radical Biol. Med. 1987, 3, 119-123.
    • (1987) Free Radical Biol. Med. , vol.3 , pp. 119-123
    • Fraga, C.G.1    Leibovitz, B.E.2    Tappel, A.K.3
  • 15
    • 0021112714 scopus 로고
    • The effect of cryosolvents on the spectral and catalytic properties of liver alcohol dehydrogenase
    • Greeves, M. A., S. C. Koerber, M. F. Dunn & A. L. Fink: The effect of cryosolvents on the spectral and catalytic properties of liver alcohol dehydrogenase. J. Biol. Chem. 1983, 258, 12184-12189.
    • (1983) J. Biol. Chem. , vol.258 , pp. 12184-12189
    • Greeves, M.A.1    Koerber, S.C.2    Dunn, M.F.3    Fink, A.L.4
  • 16
    • 0019808974 scopus 로고
    • Role of 2-haloethylene oxides and 2-haloacetaldehyde derived from vinyl bromide and vinyl chloride in irreversible binding to protein and DNA
    • Guengerich, F. P., P. S. Mason, W. T. Stott, T. R. Fox & P. G. Watanabe: Role of 2-haloethylene oxides and 2-haloacetaldehyde derived from vinyl bromide and vinyl chloride in irreversible binding to protein and DNA. Cancer Res. 1981, 41, 4391-4398.
    • (1981) Cancer Res. , vol.41 , pp. 4391-4398
    • Guengerich, F.P.1    Mason, P.S.2    Stott, W.T.3    Fox, T.R.4    Watanabe, P.G.5
  • 17
    • 0027934462 scopus 로고
    • Inhibition of p-nitrophenol hydroxylase in rat liver microsomes by small aromatic and heterocyclic molecules
    • Hargreaves, M. B., B. C. Jones, D. A. Smith & A. Gesher: Inhibition of p-nitrophenol hydroxylase in rat liver microsomes by small aromatic and heterocyclic molecules. Drug Metab. Disp. 1994, 22, 806-810.
    • (1994) Drug Metab. Disp. , vol.22 , pp. 806-810
    • Hargreaves, M.B.1    Jones, B.C.2    Smith, D.A.3    Gesher, A.4
  • 18
    • 0014661454 scopus 로고
    • Formation of ethylene bromohydrin in fluor and wheat during treatment with ethylene oxide
    • Heuser, S. G. & K. S. Scudamore: Formation of ethylene bromohydrin in fluor and wheat during treatment with ethylene oxide. Chem. Ind. 1969, 31, 1054-1055.
    • (1969) Chem. Ind. , vol.31 , pp. 1054-1055
    • Heuser, S.G.1    Scudamore, K.S.2
  • 19
    • 0019766946 scopus 로고
    • Comparative metabolism of 2-bromoethanol and ethylene oxide in the rat
    • Jones, A. R. & G. Wells: Comparative metabolism of 2-bromoethanol and ethylene oxide in the rat. Xenobiotica 1981, 11, 763-770.
    • (1981) Xenobiotica , vol.11 , pp. 763-770
    • Jones, A.R.1    Wells, G.2
  • 20
    • 0024721260 scopus 로고
    • Hepatic fatty acid conjugation of 2-chloroethanol and 2-bromoethanol in rats
    • Kaphalia, B. S. & G. A. S. Ansari: Hepatic fatty acid conjugation of 2-chloroethanol and 2-bromoethanol in rats. J. Biochem. Toxicol. 1989, 4, 183-188.
    • (1989) J. Biochem. Toxicol. , vol.4 , pp. 183-188
    • Kaphalia, B.S.1    Ansari, G.A.S.2
  • 21
    • 0016719209 scopus 로고
    • Superoxide, hydrogen peroxide and singlet oxygen in lipid peroxidation by a xanthine oxidase system
    • Kellog, E. W. & I. Fridovich: Superoxide, hydrogen peroxide and singlet oxygen in lipid peroxidation by a xanthine oxidase system. J. Biol. Chem. 1975, 250, 8812-8817.
    • (1975) J. Biol. Chem. , vol.250 , pp. 8812-8817
    • Kellog, E.W.1    Fridovich, I.2
  • 22
    • 0026094923 scopus 로고
    • 1-Bromoalkanes as new potent nontoxic glutathione depleters in isolated rat hepatocytes
    • Khan, S. & P. J. O'Brien: 1-Bromoalkanes as new potent nontoxic glutathione depleters in isolated rat hepatocytes. Biochem. Biophys. Res. Commun. 1991, 179, 436-441.
    • (1991) Biochem. Biophys. Res. Commun. , vol.179 , pp. 436-441
    • Khan, S.1    O'Brien, P.J.2
  • 23
    • 0027397660 scopus 로고
    • Molecular mechanisms of dibromoalkane cytotoxicity in isolated rat hepatocytes
    • Khan, S., C. Sood & P. J. O'Brien: Molecular mechanisms of dibromoalkane cytotoxicity in isolated rat hepatocytes. Biochem. Pharmacol. 1993, 45, 439-447.
    • (1993) Biochem. Pharmacol. , vol.45 , pp. 439-447
    • Khan, S.1    Sood, C.2    O'Brien, P.J.3
  • 24
    • 0020046192 scopus 로고
    • Comparison of the mutagenic potency of 2-chloroethanol, 2-bromoethanol, 1,2-epoxybutane, epichlorohydrin and glycidaldehyde in Klebsiella pneumoniae. Drosophila melanogaster and L5178Y mouse lymphoma cells
    • Knaap, M. A. G. A., C. E. Voogd & P. G. N. Kramers: Comparison of the mutagenic potency of 2-chloroethanol, 2-bromoethanol, 1,2-epoxybutane, epichlorohydrin and glycidaldehyde in Klebsiella pneumoniae. Drosophila melanogaster and L5178Y mouse lymphoma cells. Mut. Res. 1980, 101, 199-208.
    • (1980) Mut. Res. , vol.101 , pp. 199-208
    • Knaap, M.A.G.A.1    Voogd, C.E.2    Kramers, P.G.N.3
  • 25
    • 0021673514 scopus 로고
    • Stereochemical studies on the cytochrome P-450 and hydroxy radical dependent pathway of 2-butanol oxidation by microsomes from chow-fed, phenobarbital-treated, and ethanol-treated rats
    • Krikun, G. & A. I. Cederbaum: Stereochemical studies on the cytochrome P-450 and hydroxy radical dependent pathway of 2-butanol oxidation by microsomes from chow-fed, phenobarbital-treated, and ethanol-treated rats. Biochemistry 1984, 23, 5489-5494.
    • (1984) Biochemistry , vol.23 , pp. 5489-5494
    • Krikun, G.1    Cederbaum, A.I.2
  • 26
    • 0019961364 scopus 로고
    • Protective effect of diethyldithiocarbamate and carbon disulfide against liver injury induced by various hepatotoxic agents
    • Masuda, Y. & N. Nakayama: Protective effect of diethyldithiocarbamate and carbon disulfide against liver injury induced by various hepatotoxic agents. Biochem. Pharmacol. 1982, 31, 2713-2725.
    • (1982) Biochem. Pharmacol. , vol.31 , pp. 2713-2725
    • Masuda, Y.1    Nakayama, N.2
  • 27
    • 0003601534 scopus 로고
    • Merck & Co., Rahway, New Jersey, 9th edition
    • Merck Index: Ed.: M. Windholz. Merck & Co., Rahway, New Jersey, 1976, 9th edition, P. 499.
    • (1976) Merck Index , pp. 499
    • Windholz, M.1
  • 29
    • 84990000527 scopus 로고
    • The metabolism of ethylene bromide in the rat. I. Identification of detoxification products in urine
    • Nachtomi, E., E. Alumot & A. Bondi: The metabolism of ethylene bromide in the rat. I. Identification of detoxification products in urine. Isr. J. Chem. 1956, 4, 239-246.
    • (1956) Isr. J. Chem. , vol.4 , pp. 239-246
    • Nachtomi, E.1    Alumot, E.2    Bondi, A.3
  • 30
    • 0343129181 scopus 로고
    • Molecular mechanisms for the envolvement of the aldehydic metabolites of lipid peroxides in cytotoxicity and carcinogenesis
    • Ed.: J. J. Kabara. The American Oil Chemists Society, Champaign, IL
    • O'Brien, P. J., H. Kaul, L. McGirr & J. M. Silva: Molecular mechanisms for the envolvement of the aldehydic metabolites of lipid peroxides in cytotoxicity and carcinogenesis. In: Pharmacological effects of lipids III. Ed.: J. J. Kabara. The American Oil Chemists Society, Champaign, IL, 1988, pp. 266-280.
    • (1988) Pharmacological Effects of Lipids III , pp. 266-280
    • O'Brien, P.J.1    Kaul, H.2    McGirr, L.3    Silva, J.M.4
  • 32
    • 49749195252 scopus 로고
    • Interaction of ascorbic acid and mitochondrial lipids
    • Ottolenghi, A.: Interaction of ascorbic acid and mitochondrial lipids. Arch. Biochem. Biophys. 1959, 79, 355-361.
    • (1959) Arch. Biochem. Biophys. , vol.79 , pp. 355-361
    • Ottolenghi, A.1
  • 33
    • 0023854288 scopus 로고
    • Characterization and identification of a pyrazole-inducible form of cytochrome P-450
    • Palakodety, R. B., L. A. Cleran, G. Krikun, D. E. Feierman & A. I. Cederbaum: Characterization and identification of a pyrazole-inducible form of cytochrome P-450. J. Biol. Chem. 1988, 263, 878-884.
    • (1988) J. Biol. Chem. , vol.263 , pp. 878-884
    • Palakodety, R.B.1    Cleran, L.A.2    Krikun, G.3    Feierman, D.E.4    Cederbaum, A.I.5
  • 34
    • 0027476657 scopus 로고
    • Bioactivation of halogenated hydrocarbons by cytochrome P4502E1
    • Raucy, J. L., J. C. Kraner & J. M. Lasker: Bioactivation of halogenated hydrocarbons by cytochrome P4502E1. Crit. Rev. Toxicol. 1993, 23, 1-20.
    • (1993) Crit. Rev. Toxicol. , vol.23 , pp. 1-20
    • Raucy, J.L.1    Kraner, J.C.2    Lasker, J.M.3
  • 35
    • 0019131878 scopus 로고
    • High performance liquid chromatography analysis of nanomoles levels of glutathione, glutathione disulfide, and related thiols and disulfides
    • Reed, D. J., J. R. Babson, B. W. Beaty, A. E. Brodie, W. W. Ellis & D. N. Potter: High performance liquid chromatography analysis of nanomoles levels of glutathione, glutathione disulfide, and related thiols and disulfides. Anal. Biochem. 1980, 106, 55-62.
    • (1980) Anal. Biochem. , vol.106 , pp. 55-62
    • Reed, D.J.1    Babson, J.R.2    Beaty, B.W.3    Brodie, A.E.4    Ellis, W.W.5    Potter, D.N.6
  • 36
    • 0015510544 scopus 로고
    • Mechanism of allyl alcohol-induced hepatic necrosis
    • Reid, W. D.: Mechanism of allyl alcohol-induced hepatic necrosis. Experentia 1972, 28, 1058-1061.
    • (1972) Experentia , vol.28 , pp. 1058-1061
    • Reid, W.D.1
  • 37
    • 0028125917 scopus 로고
    • Dithiothreitol reversal of allyl alcohol cytotoxicity in isolated rat hepatocytes
    • Rians, L. E. & Y. Cai: Dithiothreitol reversal of allyl alcohol cytotoxicity in isolated rat hepatocytes. Toxicology 1994, 86, 147-161.
    • (1994) Toxicology , vol.86 , pp. 147-161
    • Rians, L.E.1    Cai, Y.2
  • 38
    • 0017687255 scopus 로고
    • Steric factors in the inhibitory interaction of imidazoles with microsomal enzymes
    • Rogerson, T. D., C. F. Wilkinson & K. Hetarska: Steric factors in the inhibitory interaction of imidazoles with microsomal enzymes. Biochem. Pharmacol. 1977, 26, 1039-1042.
    • (1977) Biochem. Pharmacol. , vol.26 , pp. 1039-1042
    • Rogerson, T.D.1    Wilkinson, C.F.2    Hetarska, K.3
  • 39
    • 0016207176 scopus 로고
    • 2-Haloethanols: Mutagenicity and reactivity with DNA
    • Rosenkranz, S., H. S. Carr & H. S. Rosenkranz: 2-Haloethanols: Mutagenicity and reactivity with DNA. Mut. Res. 1974, 26, 367-370.
    • (1974) Mut. Res. , vol.26 , pp. 367-370
    • Rosenkranz, S.1    Carr, H.S.2    Rosenkranz, H.S.3
  • 40
    • 0023100571 scopus 로고
    • Acetaldehyde-mediated hepatic lipid peroxidation: Role of superoxide and ferritin
    • Shaw, S. & E. Jayatilleke: Acetaldehyde-mediated hepatic lipid peroxidation: Role of superoxide and ferritin. Biochem. Biophys. Res. Commun. 1987, 143, 984-900.
    • (1987) Biochem. Biophys. Res. Commun. , vol.143 , pp. 984-1900
    • Shaw, S.1    Jayatilleke, E.2
  • 41
    • 0024820787 scopus 로고
    • Allyl alcohol- and acrolein-induced toxicity in isolated rat hepatocytes
    • Silva, J. & P. J. O'Brien: Allyl alcohol- and acrolein-induced toxicity in isolated rat hepatocytes. Arch. Biochem. Biophys. 1989, 275, 551-558.
    • (1989) Arch. Biochem. Biophys. , vol.275 , pp. 551-558
    • Silva, J.1    O'Brien, P.J.2
  • 42
    • 0020058754 scopus 로고
    • The measurement of lipid peroxidation in isolated hepatocytes
    • Smith, M. T., H. Thor, P. Hartzell & S. Orrenius: The measurement of lipid peroxidation in isolated hepatocytes. Biochem. Pharmacol. 1982, 31, 19-26.
    • (1982) Biochem. Pharmacol. , vol.31 , pp. 19-26
    • Smith, M.T.1    Thor, H.2    Hartzell, P.3    Orrenius, S.4
  • 43
    • 0027431867 scopus 로고
    • Molecular mechanisms of chloroacetaldehyde-induced cytotocity in isolated rat hepatocytes
    • Sood, C. & P. J. O'Brien: Molecular mechanisms of chloroacetaldehyde-induced cytotocity in isolated rat hepatocytes. Biochem. Pharmacol. 1993, 46, 1621-1626.
    • (1993) Biochem. Pharmacol. , vol.46 , pp. 1621-1626
    • Sood, C.1    O'Brien, P.J.2
  • 44
    • 0016703095 scopus 로고
    • Hepatic microsomal alcohol-oxidazing system: Affinity for methanol, ethanol, propanol and butanol
    • Teschke, R., Y. Hasumura & C. S. Lieber: Hepatic microsomal alcohol-oxidazing system: Affinity for methanol, ethanol, propanol and butanol. J. Biol. Chem. 1975, 18, 7397-7404.
    • (1975) J. Biol. Chem. , vol.18 , pp. 7397-7404
    • Teschke, R.1    Hasumura, Y.2    Lieber, C.S.3
  • 45
    • 0023851702 scopus 로고
    • Identification of the cysteine residue in the active site of horse liver mitochondrial aldehyde dehydrogenase
    • Tu, S. C. & H. Weiner: Identification of the cysteine residue in the active site of horse liver mitochondrial aldehyde dehydrogenase. J. Biol. Chem. 1988, 263, 1212-1217.
    • (1988) J. Biol. Chem. , vol.263 , pp. 1212-1217
    • Tu, S.C.1    Weiner, H.2
  • 46
  • 47
    • 0019793477 scopus 로고
    • The influence of disulfiram and other inhibitors of oxidative metabolism on the formation of 2-hydroxy-ethyl-mercapturic acid from 1,2-dibromo-ethane by the rat
    • van Bladeren, P. J., J. J. Hoogeterp, D. D. Breimer & A. van der Gen: The influence of disulfiram and other inhibitors of oxidative metabolism on the formation of 2-hydroxy-ethyl-mercapturic acid from 1,2-dibromo-ethane by the rat. Biochem. Pharmacol. 1981, 30, 2983-2987.
    • (1981) Biochem. Pharmacol. , vol.30 , pp. 2983-2987
    • Van Bladeren, P.J.1    Hoogeterp, J.J.2    Breimer, D.D.3    Van Der Gen, A.4
  • 49
    • 0023889463 scopus 로고
    • Effect of 1,2-dibromoethane on isolated hepatocytes: Functional alterations and induction of lipid peroxidation
    • van Iersel, A. A. J., I. van Holsteijn & B. J. Blaauboer: Effect of 1,2-dibromoethane on isolated hepatocytes: Functional alterations and induction of lipid peroxidation. Xenobiotica 1988, 18, 675-683.
    • (1988) Xenobiotica , vol.18 , pp. 675-683
    • Van Iersel, A.A.J.1    Van Holsteijn, I.2    Blaauboer, B.J.3
  • 50
    • 0025742702 scopus 로고
    • Modification of hepatic vitamin E stores in vivo. III. Vitamin E depletion by 1,2-dibromoethane may be related to initial conjugation with glulathione
    • Warren, D. L. & D. J. Reed: Modification of hepatic vitamin E stores in vivo. III. Vitamin E depletion by 1,2-dibromoethane may be related to initial conjugation with glulathione. Arch. Biochem. Biophys. 1991, 288, 449-455.
    • (1991) Arch. Biochem. Biophys. , vol.288 , pp. 449-455
    • Warren, D.L.1    Reed, D.J.2
  • 51
    • 0022770067 scopus 로고
    • The in vitro metabolism and bioactivation of 1,2-dibromoethane (ethylene dibromide) by human liver
    • Wiersma, D. A., R. G. Schnellmann & I. G. Sipes: The in vitro metabolism and bioactivation of 1,2-dibromoethane (ethylene dibromide) by human liver. J. Biochem. Toxicol. 1986, 1, 1-11.
    • (1986) J. Biochem. Toxicol. , vol.1 , pp. 1-11
    • Wiersma, D.A.1    Schnellmann, R.G.2    Sipes, I.G.3


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