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PROTECTIVE EFFECTS OF RESVERATROL ON
HEPATOTOXICITY INDUCED BY ANTITUBERCULOSIS DRUGS
V Mostra de
Pesquisa da PósGraduação
1, 5
Nicoletti, F.N.; 1, 5Santos, A.A. Jr; 2, 5Rodrigues-Junior, V. S.; 2,3Campos, M.M.; 5Dias, A. C. O.;
4
Leite, C. E.; 1,5Basso, L. A.; 2,5Santos, D.S.; 1,5Souto, A.A.
1
Programa de Pós-Graduação em Biologia Celular e Molecular, 2Programa de Pós-Graduação em
Medicina e Ciências da Saúde, 3Faculdade de Farmácia, 4Instituto de Toxicologia, 5Instituto Nacional de
Ciência e Tecnologia em Tuberculose, PUCRS, Porto Alegre, RS.
Introduction: Tuberculosis (TB) is a major infectious disease that causes nearly two million
deaths every year. Isoniazid (INH) and rifampin (RIF) are first line drugs used to prevent and
treat TB. RIF has been extensively reported to exacerbate the hepatotoxicity caused by INH in
patients with TB. Anti-TB drug-induced hepatotoxicity causes substantial morbidity and
diminishes treatment effectiveness because they contribute to non-adherence, treatment
failure and the emergence of drug-resistance (Tostmann et al., 2008). Resveratrol (RSV) is a
naturally occurring polyphenol with significant anti-inflammatory and antioxidant properties.
Moreover, hepatoprotective effects for RSV have been previously demonstrated (Baur et al.,
2006). In this work we have investigated the effects of RSV in the hepatotoxicity caused by
INH and RIF in mice. Methods: All the experimental protocols were approved by the local
Animal Ethics Committee (09/00107). Mice were distributed into four groups: (i) control, (ii)
RSV-treated control, (iii) INH-RIF, and (iv) RSV-treated + INH-RIF. Liver damage was
acutely induced by dosing INH (50 mg/kg) and RIF (100 mg/kg) in male BALB/c mice (25–
30 g), both p.o., for three consecutive days. RSV (100 mg/Kg) was administered orally 30
min prior to INH-RIF administration, and 2 times daily, each 6 h, until the third day after
hepatotoxicity induction. Serum biochemical tests for liver function, histopathological
examination, oxidative stress tests and myeloperoxidase (MPO) activity of liver tissues were
determined. Results: Treatment of mice with INH+RIF induced hepatotoxicity as it was
evidenced by elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase
(AST). Histopathological examination of liver tissue showed steatosis and increased apoptosis
in the animals that received anti-TB drugs, which was accompanied by a marked increase of
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tissue MPO activity. As expected, catalase and glutathione activities were found to be reduced
by INH-RIF treatment. The administration of RSV significantly decreased ALT and AST
levels (58 ± 4 % and 36 ± 8 %, respectively), as well as the MPO activity (19 ± 3 %).
Furthermore, the treatment with RSV completely reverted the decrease of both catalase and
glutathione activities, and generally ameliorated the histopathological alterations associated to
hepatotoxicity evoked by anti-TB drugs. Discussion: Recent data pointed out RSV as an
antioxidant and anti-inflammatory agent able to prevent acetaminophen-induced hepatic
failure in mice. Other studies show that RSV reduced mortality and liver damage induced by
alcohol and partial hepatectomy in rats. In conclusion, the present study demonstrates, for the
first time, that RSV protects against hepatotoxicity induced by INH-RIF. It is tempting to
suggest that this natural compound might be useful for the treatment of liver injury due to
anti-TB drugs.
Financial support: CNPq-INCT, BNDES.
Referências
TOSTMANN A., BOEREE M.J., AARNOUTSE R.E., LANGE W.C.M., VAN DER VEN A.J.A.M.,
DEKHUIJZEN R. Antituberculosis drug-induced hepatotoxicity: Consise up-to-date review. Gastroenterol
Hepatol. Vol 23 (2008), pp. 192-202.
BAUR J.A., SINCLAIR D.A. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov.
Vol. 5 ( 2006), pp. 493-506.
V Mostra de Pesquisa da Pós-Graduação – PUCRS, 2010