ELECTROPHILE AND ANTIOXIDANT REGULATION OF ENZYMES THAT DETOXIFY CARCINOGENS

被引:210
作者
PRESTERA, T [1 ]
TALALAY, P [1 ]
机构
[1] JOHNS HOPKINS UNIV, SCH MED, DEPT PHARMACOL & MOLEC SCI, BALTIMORE, MD 21205 USA
关键词
ELECTROPHILE- AND ANTIOXIDANT-RESPONSIVE ELEMENTS; AP-1; PHORBOL ESTER-RESPONSIVE ELEMENT; CHEMOPROTECTION; PHASE; 2; ENZYMES;
D O I
10.1073/pnas.92.19.8965
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Detoxication (phase 2); enzymes, such as glutathione S-transferases (GSTs), NAD(P)H: (quinone-acceptor) oxidoreductase (QR), and UDP-glucuronosyltransferase, are induced in animal cells exposed to a variety of electrophilic compounds and phenolic antioxidants. Induction protects against the toxic and neoplastic effects of carcinogens and is mediated by activation of upstream electrophile-responsive/antioxidant-responsive elements (EpRE/ARE), The mechanism of activation of these enhancers was analyzed by transient gene expression of growth hormone reporter constructs containing a 41-bp region derived from the-mouse GST Ya gene 5'-upstream region that contains the EpRE/ARE element and of constructs in which this element was replaced with either one or two consensus phorbol 12-tetradecanoate 13-acetate (TPA)-responsive elements (TREs). When these three constructs were compared in Hep G2 (human) and Hepa 1c1c7 (murine) hepatoma cells, the wild-type sequence nas highly activated by diverse inducers, including tert-butylhydroquinone, Michael reaction acceptors,1,2-dithiole-3-thione, sulforaphane, 2,3-dimercapto-1-propanol, HgCl2, sodium arsenite, and phenylarsine oxide, In contrast, constructs with consensus TRE sites were not induced significantly, TPA in combination with these compounds led to additive or synergistic inductions of the EpRE/ARE construct, but induction of the TRE construct was similar to that induced by TPA alone, Transfection of the EpRE/ARE reporter construct into F9 cells, which lack endogenous TRE binding proteins, produced large inductions by the same compounds, which also induced QR activity in these cells, We conclude that activation of the EpRE/ARE by electrophile and antioxidant inducers is mediated by EpRE/ARE-specific proteins.
引用
收藏
页码:8965 / 8969
页数:5
相关论文
共 38 条