Chemical and molecular regulation of enzymes that detoxify carcinogens
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 enhances 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., HgCl[sub 2] and CdCl[sub 2]; 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[prime] upstream region of the mouse liver glutathione transferase Ya subunit gene ligated to the 5[prime] 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 [open quotes]AP-1 like[close quotes] 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. 33 refs., 4 figs., 2 tabs.
- OSTI ID:
- 6199883
- Journal Information:
- Proceedings of the National Academy of Sciences of the United States of America; (United States), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (United States) Vol. 90:7; ISSN PNASA6; ISSN 0027-8424
- Country of Publication:
- United States
- Language:
- English
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560300 -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
ARSENIC
BIOCHEMISTRY
CARCINOGENS
CHEMISTRY
COENZYMES
DETOXIFICATION
DRUGS
ELEMENTS
ENZYMES
GLUTATHIONE
HALIDES
HALOGEN COMPOUNDS
HYDROGEN COMPOUNDS
HYDROGEN PEROXIDE
ISOTHIOCYANATES
NAD
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
OXYGEN COMPOUNDS
PEPTIDES
PEROXIDES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
SEMIMETALS
TRANSCRIPTION
TRANSFERASES