Protective effects of kaempferol on isoniazid- and rifampicin-induced hepatotoxicity

Tung Yuan Shih, Ton Ho Young, Herng Sheng Lee, Chung Bao Hsieh, Oliver Yoa Pu Hu

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Isoniazid (INH) and rifampicin (RIF) are the first-line drugs for antituberculosis (anti-TB) chemotherapy. The levels of serum transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] are abnormal in 27% of patients undergoing INH and RIF treatments and in 19% of patients undergoing treatment with INH alone. Cytochrome P450 2E1 (CYP2E1) metabolizes many toxic substrates, including ethanol, carbon tetrachloride, and INH, which ultimately results in liver injury. The objective of this study was to screen for CYP2E1 inhibitors in vitro and investigate whether the selected compound could prevent INH/RIF-induced hepatotoxicity in vivo. We screened 83 known compounds from food and herbal medicines as inhibitors of CYP2E1. The hepatotoxic dose of INH/RIF was 50/100 mg kg-1 day-1. Hepatotoxicity was assessed using galactose single-point (GSP) method (a quantitative measurement of liver function), histopathological examination of the liver, malondialdehyde (MDA) assay, and measurement of AST and ALT activities. Kaempferol inhibited CYP2E1 activity in mice by 0.31- to 0.48-fold (p < 0.005). Mice with INH/RIF-induced hepatotoxicity showed significantly abnormal serum levels of AST and ALT, and GSP value, and these values could be decreased by the administration of kaempferol (p < 0.005). Kaempferol significantly reduced the depletion of hepatic glutathione and prevented the increase in MDA formation in mice. Furthermore, kaempferol did not affect the anti-TB effects of INH/RIF. To our knowledge, this is the first report of kaempferol's utility as an adjuvant for preventing CYP2E1-mediated hepatotoxicity induced by drugs such as INH and RIF.

Original languageEnglish
Pages (from-to)753-762
Number of pages10
JournalAAPS Journal
Volume15
Issue number3
DOIs
Publication statusPublished - Jul 1 2013
Externally publishedYes

Fingerprint

Isoniazid
Rifampin
Cytochrome P-450 CYP2E1
Aspartate Aminotransferases
Alanine Transaminase
Liver
Malondialdehyde
Galactose
Carbon Tetrachloride
Herbal Medicine
Poisons
Transaminases
kaempferol
Serum
Pharmaceutical Preparations
Glutathione
Ethanol
Drug Therapy
Food
Wounds and Injuries

Keywords

  • galactose single-point method
  • hepatotoxicity
  • isoniazid
  • kaempferol
  • rifampicin

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Shih, T. Y., Young, T. H., Lee, H. S., Hsieh, C. B., & Hu, O. Y. P. (2013). Protective effects of kaempferol on isoniazid- and rifampicin-induced hepatotoxicity. AAPS Journal, 15(3), 753-762. https://doi.org/10.1208/s12248-013-9490-6

Protective effects of kaempferol on isoniazid- and rifampicin-induced hepatotoxicity. / Shih, Tung Yuan; Young, Ton Ho; Lee, Herng Sheng; Hsieh, Chung Bao; Hu, Oliver Yoa Pu.

In: AAPS Journal, Vol. 15, No. 3, 01.07.2013, p. 753-762.

Research output: Contribution to journalArticle

Shih, Tung Yuan ; Young, Ton Ho ; Lee, Herng Sheng ; Hsieh, Chung Bao ; Hu, Oliver Yoa Pu. / Protective effects of kaempferol on isoniazid- and rifampicin-induced hepatotoxicity. In: AAPS Journal. 2013 ; Vol. 15, No. 3. pp. 753-762.
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