Atividade quimiopreventiva da tributirina na hepatocarcinogênese em ratos

Abstract

KUROIWA-TRZMIELINA, J. Chemopreventive activity of tributyrin in hepatocarcinogenesis in rats. 2007. 167 p. Master’s degree dissertation – Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, 2007. Chemopreventive activity of tributyrin (T), a butyric acid prodrug found in milk and its derivatives, was evaluated during the initial phases of the “Resistant Hepatocyte” (RH) model of hepatocarcinogenesis. During 8 consecutive weeks, rats received T (200 mg/100 g body weight; TB group) or maltodextrin (M; 300 mg/100 g body weight; MD group; isocaloric control). Two weeks after the beginning of the treatments, the animals received one dose of diethylnitrosamine (DEN; 20 mg/100 g body weight) for initiation. Two weeks later, the animals received six doses of 2acetylaminofluorene (AAF, 2 mg/100 g body weight), 4 consecutive doses before partial (2/3) hepatectomy and the remaining, two and four days after surgery. All animals were euthanized 6 weeks after DEN administration. Two hours before euthanasia, rats received 5-bromo-2-desoxiuridina (BrdU) (10 mg/100 g body weight). Multiplicity and area of visible hepatocyte nodules/animal were smaller (p 0,05) were observed between MD and TB groups regarding cell proliferation and DNA damage. TB group presented reduced (p < 0,05) % of total and persistant PNL p53 positive compared to MD group. TB group presented reduced (p < 0,05) nuclear factor-κB (NF-κB) activation in comparison with MD group. Lysine 9 acetylation site in H3 (H3K9) tended to be increased in TB group compared to MD. These results indicate that T represents promising chemopreventive agent against hepatocarcinogenesis when administered to Wistar rats during 8 consecutive weeks on initial phases of RH model. Persistant hepatic GST-P positive PNL inhibition, remodeling and apoptosis induction, p53 function normalization, inhibition of NF-κB activation and H3K9 acetylation can be involved with antineoplastic T actions. Key-words: chemoprevention, hepatocarcinogenesis, tributyrin, p53, NF-κB, histone.