Environmental Health Perspectives 105, Supplement 1, February 1997

Chemoprevention by Inducers of Carcinogen Detoxication Enzymes

Thomas W. Kensler

Department of Environmental Health Sciences, The Johns Hopkins University, Baltimore, Maryland

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 , µ and 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 hepatocellular carcinoma, is currently under evaluation. -- Environ Health Perspect 105(Suppl 4):965-970 (1997)

Key words: glutathione S-transferases, NAD(P)H:quinone reductase, enzyme induction, oltipraz, 1,2-dithiole-3-thione, aflatoxin B1, biomarkers

This paper is based on a presentation at the symposium on Mechanisms and Prevention of Environmentally Caused Cancers held 21-25 October 1995 in Santa Fe, New Mexico. Manuscript received at EHP 16 April 1996; accepted 20 September 1996.
The author gratefully acknowledges the contributions of numerous colleagues to the oltipraz experimental and clinical studies. Financial support for our studies on cancer chemoprevention comes from the National Institutes of Health (CA39416, CA44530, CA-N01-CN-25437, and ES06052, and Center Grant ES03819).
Address correspondence to Dr. T.W. Kensler, Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, 615 N. Wolfe Street, Baltimore, MD 21205. Telephone: (410) 955-4712. Fax: (410) 955-0116. E-mail: tkensler@phnet.sph.jhu.edu
Abbreviations used: AFB1, aflatoxin B1; Ah, aryl hydrocarbon; BHA, butylated hydroxyanisole; BHT, butylated hydroxytoluene; GST, glutathione S-transferase.

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Last Update: June 30, 1997