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Chemoprevention by inducers of carcinogen detoxication enzymes
1Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland 21205, USA. tkensler@phnet.sph.jhu.edu
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.
Insights
Oltipraz, a chemopreventive agent, effectively inhibits aflatoxin-induced liver cancer in rats by boosting protective phase 2 enzymes like glutathione S-transferases (GSTs). Intermittent dosing shows promise for cancer prevention.
Area of Science:
- Biochemistry
- Toxicology
- Chemoprevention
Background:
- Electrophilic toxicity, including carcinogenesis and mutagenesis, is countered by inducing phase 2 metabolic enzymes.
- Glutathione S-transferases (GSTs) are key phase 2 enzymes involved in detoxifying electrophiles.
- 1,2-dithiole-3-thiones are a class of chemopreventive agents known for inducing GSTs.
Purpose of the Study:
- To evaluate the efficacy of oltipraz, a substituted dithiolethione, in inhibiting aflatoxin B1-mediated hepatocarcinogenesis in rats.
- To investigate the molecular mechanisms underlying oltipraz's chemopreventive effects, focusing on phase 2 enzyme induction.
Main Methods:
- Administration of oltipraz to rats exposed to aflatoxin B1.
- Measurement of aflatoxin-DNA adducts and metabolites in liver and urine.
- Assay of hepatic GST activities and mRNA levels for various GST isoforms.
- Nuclear run-on assays to assess GST gene transcription rates.
- Analysis of the role of the antioxidant response element in mediating enzyme induction.
Main Results:
- Oltipraz significantly reduced aflatoxin-DNA adducts and urinary aflatoxin metabolites.
- Biliary elimination of aflatoxin-glutathione conjugates increased following oltipraz administration.
- Hepatic GST activities and mRNA levels for specific GST isoforms increased 3- to 4-fold.
- Oltipraz elevated transcription rates of some GST subunits, partly mediated by the antioxidant response element.
- GST induction persisted for up to a week after dosing, allowing for effective intermittent dosing schedules.
Conclusions:
- Oltipraz is a potent inhibitor of aflatoxin B1-induced hepatocarcinogenesis in rats.
- The chemopreventive effect is mediated by the induction of phase 2 enzymes, particularly GSTs.
- Intermittent dosing of oltipraz is effective due to the sustained induction of GSTs, suggesting potential for human chemoprevention strategies.