TY - JOUR
T1 - Chemical and molecular regulation of enzymes that detoxify carcinogens
AU - Prestera, Tory
AU - Holtzclaw, W. David
AU - Zhang, Yuesheng
AU - Talalay, Paul
PY - 1993/4/1
Y1 - 1993/4/1
N2 - Inductions of detoxication (phase 2) enzymes, such as glutathione transferases and NAD(P)H:(quinone-acceptor) oxidoreductase, are a major mechanism for protecting animals and their cells against the toxic and neoplastic effects of carcinogens. These inductions result from enhanced transcription, and they are evoked by diverse chemical agents: oxidizable diphenols and phenylenediamines; Michael reaction acceptors; organic isothiocyanates; other electrophiles - e.g., alkyl and aryl halides; metal ions - e.g., HgCl2 and CdCl2; trivalent arsenic derivatives; vicinal dimercaptans; organic hydroperoxides and hydrogen peroxide; and 1,2-dithiole-3-thiones. The molecular mechanisms of these inductions were analyzed with the help of a construct containing a 41-bp enhancer element derived from the 5′ upstream region of the mouse liver glutathione transferase Ya subunit gene ligated to the 5′ end of the isolated promoter region of this gene, and inserted into a plasmid containing a human growth hormone reporter gene. When this construct was transfected into Hep G2 human hepatoma cells, the concentrations of 28 compounds (from the above classes) required to double growth hormone production, and the concentrations required to double quinone reductase specific activities in Hepa 1c1c7 cells, spanned a range of four orders of magnitude but were closely linearly correlated. Six compounds tested were inactive in both systems. A 26-bp subregion of the above enhancer oligonucleotide (containing the two tandem "AP-1-like" sites but lacking the preceding ETS protein binding sequence) was considerably less responsive to the same inducers. We conclude that the 41-bp enhancer element mediates most, if not all, of the phase 2 enzyme inducer activity of all of these widely different classes of compounds.
AB - Inductions of detoxication (phase 2) enzymes, such as glutathione transferases and NAD(P)H:(quinone-acceptor) oxidoreductase, are a major mechanism for protecting animals and their cells against the toxic and neoplastic effects of carcinogens. These inductions result from enhanced transcription, and they are evoked by diverse chemical agents: oxidizable diphenols and phenylenediamines; Michael reaction acceptors; organic isothiocyanates; other electrophiles - e.g., alkyl and aryl halides; metal ions - e.g., HgCl2 and CdCl2; trivalent arsenic derivatives; vicinal dimercaptans; organic hydroperoxides and hydrogen peroxide; and 1,2-dithiole-3-thiones. The molecular mechanisms of these inductions were analyzed with the help of a construct containing a 41-bp enhancer element derived from the 5′ upstream region of the mouse liver glutathione transferase Ya subunit gene ligated to the 5′ end of the isolated promoter region of this gene, and inserted into a plasmid containing a human growth hormone reporter gene. When this construct was transfected into Hep G2 human hepatoma cells, the concentrations of 28 compounds (from the above classes) required to double growth hormone production, and the concentrations required to double quinone reductase specific activities in Hepa 1c1c7 cells, spanned a range of four orders of magnitude but were closely linearly correlated. Six compounds tested were inactive in both systems. A 26-bp subregion of the above enhancer oligonucleotide (containing the two tandem "AP-1-like" sites but lacking the preceding ETS protein binding sequence) was considerably less responsive to the same inducers. We conclude that the 41-bp enhancer element mediates most, if not all, of the phase 2 enzyme inducer activity of all of these widely different classes of compounds.
KW - Chemoprotection
KW - Electrophiles
KW - Phase 2 enzymes
KW - Quinone reductase
KW - Transient gene expression
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U2 - 10.1073/pnas.90.7.2965
DO - 10.1073/pnas.90.7.2965
M3 - Article
C2 - 8385353
AN - SCOPUS:0027394238
SN - 0027-8424
VL - 90
SP - 2965
EP - 2969
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 7
ER -