Lupeol prevents acetaminophen-induced in vivo hepatotoxicity by altering the Bax/Bcl-2 and oxidative stress-mediated mitochondrial signaling cascade.
OBJECTIVE
Lupeol, a triterpene, possesses numerous pharmacological activities, including anti-malarial, anti-arthritic and anti-carcinogenic properties. The present study was conducted to explore the hepatoprotective potential of lupeol against acetaminophen (AAP)-induced hepatotoxicity in Wistar rats.


METHODS
Rats were given a prophylactic treatment of lupeol (150 mg/kg body weight, p.o., for 30 consecutive days) with a co-administration of AAP (1 g/kg body weight). The modulatory effects of lupeol on AAP-induced hepatotoxicity were investigated by assaying oxidative stress biomarkers, serum liver toxicity markers, pro/anti apoptotic proteins, DNA fragmentation and by the histopathological examination of the liver.


RESULTS
Lupeol significantly prevented hepatic damage as evident from the histopathological studies and significant decline in serum trans-aminases. The alterations in cellular redox status (p<0.01) and antioxidant enzyme activities together with the enhanced lipid peroxidation and protein carbonyl levels were also observed in the AAP-treated rats. In addition, significant ROS generation and mitochondrial depolarization were observed in this group. Co-administration of lupeol significantly decreased the level of serum transaminases, MDA and protein carbonyl content. It also prevented ROS generation and mitochondrial depolarization. Furthermore, lupeol enhanced the mitochondrial antioxidant and redox status and inhibited DNA damage and cell death by preventing the downregulation of Bcl-2, upregulation of Bax, release of cytochrome c and the activation of caspase 9/3.


CONCLUSIONS
The conclusion of this study is that lupeol when co-administered with AAP effectively reduces oxidative stress and prevents AAP-induced hepatotoxicity by inhibiting critical control points of apoptosis.
Herbal Research Section, CSIR-Indian Institute of Toxicology Research, M.G. Marg-226001, Lucknow-226001, India.
Archana
A
Kumari
Poonam
P
Kakkar
D000082:Acetaminophen / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D016022:Case-Control Studies; D002374:Catalase / Q000378:metabolism; D053938:DNA Fragmentation; D005434:Flow Cytometry; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D053978:Pentacyclic Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013482:Superoxide Dismutase / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D000094042:Lupanes
D000082:Acetaminophen; D015415:Biomarkers; D002374:Catalase; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005982:Glutathione Transferase; D053978:Pentacyclic Triterpenes; D019253:Proto-Oncogene Proteins c-bcl-2; D013482:Superoxide Dismutase; D051028:bcl-2-Associated X Protein; C494828:Bax protein, rat; C010480:lupeol; D000094042:Lupanes