title: Effects of andrographolide on intrahepatic cholestasis induced by alpha-naphthylisothiocyanate in rats.
abstract: Cholestasis is a cardinal manifestation of liver diseases but effective therapeutic approaches are limited. Therefore, alternative therapy for treating and preventing cholestatic liver diseases is necessary. Andrographolide, a promising anticancer drug derived from the medicinal plant Andrographis paniculata, has diverse pharmacological properties and multi-spectrum therapeutic applications. However, it is unknown whether andrographolide has a hepatoprotective effect on intrahepatic cholestasis. The aims of this study were to investigate the protective effect and possible mechanisms of andrographolide in a rat model of acute intrahepatic cholestasis induced by alpha-naphthylisothiocyanate (ANIT). Andrographolide was administered intragastrically for four consecutive days, with a single intraperitoneal injection of ANIT on the second day. Liver injury was evaluated biochemically and histologically together with hepatic gene and protein expression analysis. Rats pretreated with andrographolide prior to ANIT injection demonstrated lower levels of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, as well as bilirubin and bile acids as compared to rats treated with ANIT alone. Andrographolide also decreased the incidence and extent of periductular fibrosis and bile duct proliferation. Analysis of protein expression in livers from andrographolide-treated cholestatic rats revealed markedly decreased expression of alpha-smooth muscle actin and nuclear factor kappa-B (NF-κB). In conclusion, andrographolide has a potent protective property against ANIT-induced cholestatic liver injury. The mechanisms that underlie this protective effect are mediated through down-regulation of NF-κB expression and inhibition of hepatic stellate cell activation. These findings suggest that andrographolide could be a promising therapeutic option in prevention and slowing down the progression of cholestatic liver diseases.
authors.affiliation: Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Tanaporn
authors.initials: T
authors.lastname: Khamphaya
authors.affiliation: Department of Anatomy, Phramongkutklao College of Medicine, Bangkok, Thailand.
authors.forename: Piyachat
authors.initials: P
authors.lastname: Chansela
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Pawinee
authors.initials: P
authors.lastname: Piyachaturawat
authors.affiliation: Department of Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand.
authors.forename: Apichart
authors.initials: A
authors.lastname: Suksamrarn
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Nathanson
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA. Electronic address: jittima.wee@mahidol.ac.th.
authors.forename: Jittima
authors.initials: J
authors.lastname: Weerachayaphorn
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000494:pharmacology*; D000818:Animals; D001652:Bile Ducts / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats
chemical_list: D004224:Diterpenes; D016328:NF-kappa B; D019938:Cyclin D1; C030419:andrographolide; D015058:1-Naphthylisothiocyanate
keywords: Alpha-naphthylisothiocyanate; Alpha-naphthylisothiocyanate (PubChem CID: 11080); Andrographolide; Andrographolide (PubChem CID: 5318517); Bile acid transporters; Bile duct; Carboxymethylcellulose Sodium (PubChem CID: 23706213); Cholestasis; Hepatic stellate cells