Chemoprevention by inducers of carcinogen detoxication enzymes.

Abstract

One of the major mechanisms of chemical protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by electrophiles is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases (GSTs), uridine diphosphate-glucuronosyltransferases, and NAD(P)H:quinone reductase. Furthermore, induction of phase 2 enzymes appears to be a sufficient condition for obtaining chemoprevention and can be achieved in many target tissues by administering any of a diverse array of naturally occurring and synthetic chemical agents. One class of chemopreventive agents, 1,2-dithiole-3-thiones, was developed on the basis of their potent activity in rodent tissues as inducers of GSTs. A substituted dithiolethione, oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione], is an effective inhibitor of aflatoxin B1-mediated hepatocarcinogenesis in the rat. Oltipraz produces dramatic decreases in the levels of aflatoxin-DNA adducts in the liver as well as in the urinary levels of the depurination product aflatoxin-N7-guanine. Corresponding increases are seen in the biliary elimination of aflatoxin-glutathione conjugates. Administration of oltipraz results in 3- to 4-fold increases in hepatic cytosolic GST activities and mRNA levels for some alpha, mu and pi isoforms. Nuclear run-on assays have indicated that oltipraz treatment elevates rates of transcription of some GST subunits. In the rat, induction of phase 2 enzymes by oltipraz is mediated, at least in part, through the antioxidant response element in the 5' flanking region of these genes. Although oltipraz has a very short plasma half-life, elevations in the levels of some GST isoforms can persist up to 1 week after dosing with oltipraz. Concordantly, intermittent dosing schedules (i.e., once a week) are nearly as effective as daily interventions for inhibition of aflatoxin-mediated hepatic tumorigenesis. The protective efficacy of daily and weekly administration of oltipraz to people in Qidong, People's Republic of China, who are at high risk for aflatoxin exposure and subsequent development of hepetocellular carcinoma, is currently under evaluation.

Keap1–Nrf2 Signaling: A Target for Cancer Prevention by Sulforaphane

“…In these studies, modulation of these biomarkers is presumptive evidence for a cancer risk reduction, a concept that has been well validated in animal models [26]. Multiple strategies for modifying the bioactivation and/or detoxication of environmental carcinogens have been developed [4]. Disruption of Nrf2 signaling in mice leads to increased sensitivity to carcinogenesis by environmental agents [7,27], increased burden of carcinogen-DNA adducts in target tissues [28-30] and loss of chemopreventive efficacy of anticarcinogens such as sulforaphane, oltipraz and CDDO-Im [7,27,30] and highlight a critical role for this adaptive stress response pathway as a critical determinant of susceptibility, and hence, a target for prevention.…”

“…The inducible expression of NQO1 is now recognized to be regulated principally through the Keap1-Nrf2-ARE signaling pathway [3]. This pathway in turn is an important modifier of susceptibility to electrophilic and oxidative stresses; factors central to the processes of chemical carcinogenesis and other chronic degenerative diseases [4]. Sulforaphane is a potent inducer of Nrf2 signaling and blocks the formation of dimethylbenz[a]anthracene-evoked mammary tumors in rats as well as other tumor types in various animal models [5,6].…”

Targeting NRF2 signaling for cancer chemoprevention

“…In particular, chronic inflammation is strongly associated with carcinogenesis from the perspective that elevated levels of ROS, reactive nitrogen species (RNS), cytokines, and growth factors, which are released from activated immune cells, can lead to DNA damage, cell proliferation, and cell invasiveness (Sporn and Roberts, 1986; Coussens and Werb, 2002). Based on these concepts, inhibition of these processes by increasing the expression of electrophile detoxifying enzymes and antioxidant proteins has long been postulated to be an effective way to prevent carcinogenesis (Prestera et al , 1993; Hong and Sporn, 1997; Kensler, 1997). …”

Electrophiles in Foods: The Current Status of Isothiocyanates and Their Chemical Biology

“…[11][12][13][14] Especially, electrophiles are detoxified by a group of functionally diverse phase 2 enzymes, including GSH transferases (GSTs), UDP-glucuronosyltransferases (UGTs), and NAD(P)H:quinone oxidoreductase 1 (NQO1).…”