Reduction of aflatoxin B 1 adduct biomarkers by oltipraz in the tree shrew ( Tupaia belangeri chinensis)

Abstract

The risk of liver cancer is greatest in people both infected with hepatitis B virus (HBV) and highly exposed to aflatoxin B 1 (AFB 1). The tree shrew ( Tupaia belangeri chinensis) is a unique species that can be infected with human HBV, is susceptible to AFB 1-induced liver cancer, and shows a synergistic interaction between HBV and AFB 1 for liver cancer. In this regard, the tree shrew may be useful for evaluating experimental chemoprevention strategies relevant to high-risk human populations as it mirrors the human epidemiology of liver cancer. To begin developing the model for chemoprevention study, two groups of tree shrews were fed 400 μg AFB 1/kg b.wt. in milk daily for 4 weeks. One week prior to AFB 1 administration, one group also received oltipraz (0.5 mmol/kg, p.o.) daily for 5 weeks. At weekly intervals, 1 ml of blood and a 24-h urine sample were obtained from each animal. Aflatoxin-albumin adducts in serum were determined by a radioimmunological assay and aflatoxin-N 7-guanine adducts in urine were measured by HPLC. Aflatoxin-albumin adducts increased rapidly in 2 weeks to plateau at 20 pmol/mg protein, and they diminished after cessation of AFB 1 exposure. Oltipraz significantly attenuated the overall burden of aflatoxin–albumin adducts throughout the exposure period with a median reduction of 80%. In a single cross-sectional analysis at the end of AFB 1 dosing, oltipraz treatment decreased urinary aflatoxin-N 7-guanine by 93%. Collectively, these results indicate that oltipraz reduces AFB 1 risk biomarkers in the tree shrew in a manner similar to that observed in rodents and humans, and establishes a rationale to evaluate cancer chemoprevention by oltipraz in human HBV-infected, AFB 1 exposed tree shrews.