© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 4, 347-354,
February 17, 1999
© 1999 Oxford University Press
ARTICLES |
Protective Alterations in Phase 1 and 2 Metabolism of Aflatoxin B1 by Oltipraz in Residents of Qidong, People's Republic of China
Affiliations of authors: J.-S. Wang, X. Shen, X. He, A.Zarba, P. A. Egner, J. D. Groopman, T. W. Kensler (Department of Environmental Health Sciences), L. P. Jacobson, A. Muñoz, K. J. Helzlsouer (Department of Epidemiology), The Johns Hopkins University, Baltimore, MD; Y.-R. Zhu, B.-C. Zhang, J.-B. Wang, Qidong Liver Cancer Institute, Qidong, Jiangsu Province, People's Republic of China; G.-S. Qian, S.-Y. Kuang, Shanghai Cancer Institute, Shanghai, People's Republic of China.
Correspondence to: Thomas W. Kensler, Ph.D., Department of Environmental Health Sciences, The Johns Hopkins School of Hygiene and Public Health, 615 N. Wolfe St., Baltimore, MD 21205 (e-mail: tkensler{at}jhsph.edu).
BACKGROUND: Residents of Qidong, People's Republic of China, are at high risk for development of hepatocellular carcinoma, in part due to consumption of foods contaminated with aflatoxins, which require metabolic activation to become carcinogenic. In a randomized, placebo-controlled, double-blind phase IIa chemoprevention trial, we tested oltipraz, an antischistosomal drug that has been shown to be a potent and effective inhibitor of aflatoxin-induced hepatocarcinogenesis in animal models. METHODS: In 1995, 234 adults from Qidong were enrolled. Healthy eligible individuals were randomly assigned to receive by mouth 125 mg oltipraz daily, 500 mg oltipraz weekly, or a placebo. Sequential immunoaffinity chromatography and liquid chromatography coupled to mass spectrometry or to fluorescence detection were used to identify and quantify phase 1 and phase 2 metabolites of aflatoxin B1 in the urine of study participants. Reported P values are two-sided. RESULTS: One month of weekly administration of 500 mg oltipraz led to a 51% decrease in median levels of the phase 1 metabolite aflatoxin M1 excreted in urine compared with administration of a placebo (P = .030), but it had no effect on levels of a phase 2 metabolite, aflatoxin-mercapturic acid (P = .871). By contrast, daily intervention with 125 mg oltipraz led to a 2.6-fold increase in median aflatoxin-mercapturic acid excretion (P = .017) but had no effect on excreted aflatoxin M1 levels (P = .682). CONCLUSIONS: Intermittent, high-dose oltipraz inhibited phase 1 activation of aflatoxins, and sustained low-dose oltipraz increased phase 2 conjugation of aflatoxin, yielding higher levels of aflatoxin-mercapturic acid. While both mechanisms can contribute to protection, this study highlights the feasibility of inducing phase 2 enzymes as a chemopreventive strategy in humans.
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