Kolaviron inhibits dimethyl nitrosamine-induced liver injury by suppressing COX-2 and iNOS expression via NF-kappaB and AP-1.
OBJECTIVE
Kolaviron, a bioflavonoid isolated from the seeds of Garcinia kola has been reported to possess anti-inflammatory, antioxidant, antigenotoxic and hepatoprotective activities in model systems via multiple biochemical mechanisms. The present study investigated the possible molecular mechanisms underlying the hepatoprotective effects of kolaviron.


METHODS
Biomarkers of hepatic oxidative injury, histological and immunohistochemical techniques were used. In addition, the protein expression levels of cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) were evaluated by western blotting while DNA-binding activities of nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1) were determined by electrophoretic mobility shift assay.


RESULTS
Kolaviron administered orally at doses of 100 and 200 mg/kg for 7 days significantly lowered the activities of serum transaminases and gamma-glutamyl tranferase induced by single intraperitoneal administration of dimethyl nitrosamine (DMN) (20 mg/kg) and preserved the integrity of the hepatocytes. Also, kolaviron at both doses reduced the DMN induced elevated hepatic levels of malondialdehyde and reversed DMN mediated decrease in hepatic glutathione. The hepatoprotective effect of kolaviron was compared to that of curcumin, an established hepatoprotective agent. Kolaviron inhibited the DMN induced expression of COX-2 and iNOS. Immunohistochemical staining of rat liver verified the inhibitory effect of kolaviron on DMN-induced hepatic COX-2 expression. Furthermore, kolaviron abrogated DMN induced binding activity of NF-kappaB as well as AP-1.


CONCLUSIONS
The ability of kolaviron to inhibit COX-2 and iNOS expression through down regulation of NF-kappaB and AP-1 DNA binding activities could be a mechanism for the hepatoprotective properties of kolaviron.
Farombi
Ebenezer O
EO
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea. olatunde_farombi@yahoo.com
Shrotriya
Sangeeta
S
Surh
Young-Joon
YJ
D000818:Animals; D000975:Antioxidants / Q000302:isolation & purification / Q000627:therapeutic use*; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000097:blood; D004128:Dimethylnitrosamine / Q000633:toxicity*; D024202:Electrophoretic Mobility Shift Assay; D005419:Flavonoids / Q000302:isolation & purification / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D000975:Antioxidants; D005419:Flavonoids; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D005978:Glutathione; D004128:Dimethylnitrosamine; C045492:kolaviron