Affiliations: Department of Pharmacology and Molecular Sciences, The
Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore,
MD 21205, USA. Tel.: +1 410 955 3499; Fax: +1 410 502 6818; E-mail:
ptalalay@jhmi.edu or ptalalay@aol.com
Abstract: Induction of Phase 2 enzymes is an effective and sufficient strategy
for achieving protection against the toxic and neoplastic effects of many
carcinogens. It is proposed that the concept of Phase 2 enzymes as being
responsible only for the conjugation of functionalized xenobiotics with
endogenous cellular ligands such as glutathione (glutathione S-transferases)
and glucuronic acid (UDP-glucuronosyltransferases) be expanded to include
proteins with the following common characteristics: (a) coordinate induction by
a broad range of chemical agents that all have the capacity to react with
sulfhydryl groups; (b) possible regulation by common promoter elements; and (c)
catalysis of reactions that lead to comprehensive protection against
electrophile and reactive oxygen toxicities, by a wide variety of mechanisms.
These mechanisms include: conjugation with endogenous ligands, chemical
modification of reactive features of molecules that can damage DNA and other
macromolecules, and generation or augementation of cellular antioxidants. In
addition to the above conjugating enzymes, a provisional and partial list of
Phase 2 proteins might include: NAD(P)H:quinone reductase, epoxide hydrolase,
dihydrodiol dehydrogenase, \gamma-glutamylcysteine
synthetase, heme oxygenase-1, leukotriene B_4 dehydrogenase,
aflatoxin B_1 dehydrogenase, and ferritin.
