title: Enhanced hepatic Nrf2 activation after ursodeoxycholic acid treatment in patients with primary biliary cirrhosis.
abstract: The cytoprotective mechanisms of ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC) have not been fully clarified. UDCA has some antioxidant properties. Nuclear factor-E2-related factor-2 (Nrf2) plays a critical role in protecting a variety of tissues against oxidative stress. Therefore, to investigate the potential antioxidant effects of UDCA in PBC, we determined the intracellular status of both oxidant stress and antioxidant defenses in paired pre- and posttreatment liver biopsies from 13 PBC patients by immunodetection of 8-hydroxydeoxyguanosine (8-OHdG), Nrf2-, and Nrf2-mediated antioxidant proteins. After UDCA treatment, the number of 8-OHdG-positive hepatocytes or bile duct cells decreased with improvement of hepatic injury. The hepatic levels of both total and phosphorylated Nrf2 protein were increased, along with upregulation of nuclear phosphorylated Nrf2 expression in bile duct cells. In addition, the levels of both thioredoxin (TRX) and thioredoxin reductase 1 (TrxR1) protein were increased in the liver after UDCA. The upregulation of hepatic TRX or TrxR1 protein expression positively correlated with that of total Nrf2 protein expression. In conclusion, UDCA treatment can enhance hepatic Nrf2 activation and upregulate hepatic TRX and TrxR1 protein expression. Hepatic Nrf2 activation may play a role in the therapeutic response to UDCA in PBC.
authors.affiliation: Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Kawata
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Souda
authors.forename: Kinya
authors.initials: K
authors.lastname: Kawamura
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sumiyoshi
authors.forename: Yurimi
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Hidenao
authors.initials: H
authors.lastname: Noritake
authors.forename: Shinya
authors.initials: S
authors.lastname: Watanabe
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Suehiro
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Nakamura
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001647:Bile Acids and Salts / Q000097:blood; D001706:Biopsy; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D054481:Thioredoxin Reductase 1 / Q000235:genetics / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D001647:Bile Acids and Salts; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D014580:Ursodeoxycholic Acid; D000080242:8-Hydroxy-2'-Deoxyguanosine; D054481:Thioredoxin Reductase 1; D003849:Deoxyguanosine