BIOMARKERS TO MOLECULAR INTERVENTIONS IN AFLATOXIN EXPOSED INDIVIDUALS

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Project II. Development and application of biomarkers to molecular interventions in aflatoxin-exposed individuals. A major goal of public health practice is disease prevention. Recent advances in our understanding of the fundamental mechanisms of carcinogenesis have provided opportunities to reduce human cancer incidence through molecular, chemopreventive interventions. However, use of cancer endpoints in the evaluation of new intervention strategies ensures slow and costly progress. The development of intermediate biomarkers is essential to the timely development and maturation of the field of chemoprevention. The continuing goal of these studies is to determine whether biomarkers of aflatoxicosis caused by consumption of aflatoxin-contaminated foods can be modulated by ingestion of oltipraz or chlorophyllin. Both oltipraz and chorophyllin are effective inhibitors of aflatoxin-induced hepatocarcinogenesis in animal models, although their mechanisms of action appear to be distinct. It is our hypothesis that levels of biomarkers for the biologically effective dose of aflatoxin will be predictive for assessing the efficacy of chemopreventive interventions in aflatoxin-exposed individuals. Results in rats during the initial grant period suggest that measurements of the levels of aflatoxin-N7-guanine in urine and aflatoxin-albumin adducts in serum reflect aflatoxin-induced genotoxicity in target organs. Moreover, animals fed oltipraz exhibited marked reductions in the levels of these biomarkers in parallel with reductions in the levels of hepatic aflatoxin- DNA adducts and liver cancer incidence. Molecular epidemiology studies have also firmly established these biomarkers as indices of aflatoxin exposure in humans and for subsequent risk of developing hepatocellular carcinoma. The proposed studies seek to continue the development and application of biomarkers to chemoprevention in populations at high risk for aflatoxin exposure and liver cancer. An additional biomarker of considerable promise is 8-hydroxy-2 prime- deoxyguanosine (8-OHdG). Several laboratories have shown recently that treatment of animals with aflatoxin B1 elevates levels of 8-OhdG in hepatic DNA. The proposed studies will evaluate whether measurement of 8-OHdG excretion in urine is a useful, modulatable endpoint for assessing chemopreventive efficacy. These studies will utilize urine samples collected from rats and humans that have recently undergone chemopreventive interventions with oltipraz. These studies will also be extended by conducting a clinical intervention with the anticarcinogen chlorophyllin in individuals from Qidong, Peopl~s Repubic of China, who are exposed to aflatoxins in their diets and are subsequently at high risk for development of liver cancer.