title: Effect of ammonium pyrrolidine dithiocarbamate (PDTC) on NF-κB activation and CYP2E1 content of rats with immunological liver injury.
abstract: BACKGROUND
  Ammonium pyrrolidine dithiocarbamate (PDTC) is a potent inhibitor of nuclear factor-κB (NF-κB). Recent studies have shown that NF-κB plays an essential role in the regulation of genes whose products are involved in the pathogenesis of immunological liver injury.
  
  
  OBJECTIVE
  To study the function of NF-κB in immunological liver injury of rat model and its effect on CYP2E1 content and metabolic activity.
  
  
  METHODS
  The present study investigated the effect of passivating NF-κB activation on CYP2E1 using Bacillus calmette Guérin (BCG)-induced immunological liver injury in Sprague-Dawley rats measured in terms of enzyme levels. The degree of hepatic injury of rats was measured by using biochemical parameters, hepatic tissue pathological changes, and physiological parameters. Protein localization of liver NF-κB was detected by immunohistochemical assay. Western blot analysis was used to detect the protein expression of NF-κB, IκBα, iNOS, and CYP2E1. The content of CYP2E1 of homogenate in the rat liver was detected by ELISA assay and the enzyme kinetics of CYP2E1 probe drug chlorzoxazone was evaluated by high-performance liquid chromatography (HPLC) assay.
  
  
  RESULTS
  The results showed that BCG-pretreatment (125 mg/kg) significantly (p < 0.01) increased the weight of liver and spleen (increased by 70% and 248%, respectively), serum levels of alanine transarninase (ALT) and aspartate aminotransferase (AST) (increased by 200% and 75.8%, respectively), the expression of NF-κB and iNOS (increased by 228% and 303%, respectively), and decreased CYP2E1 content and metabolic activity (p < 0.05). Administration of PDTC (50, 100, and 200 mg/kg) reversed above hepatic injury stimulated by BCG in vivo. Moreover, PDTC (ED50: 76 mg/kg) dose dependently inhibited down-regulation of CYP2E1 (p < 0.05).
  
  
  CONCLUSIONS
  Passivation of NF-κB can inhibit the down-regulation of CYP2E1 and iNOS to induce in rat liver tissue with immunological liver injury; NF-κB may be involved in the CYP2E1 regulation through iNOS.
authors: Department of Pharmacology, Baotou Medical College , Baotou , China.
authors: Jin-Dong
authors: JD
authors: Qin
authors: Zhi-Hong
authors: ZH
authors: Cao
authors: Xue-Feng
authors: XF
authors: Li
authors: Xiao-Lin
authors: XL
authors: Kang
authors: Yan
authors: Y
authors: Xue
authors: Yue-Ling
authors: YL
authors: Li
authors: Dong
authors: D
authors: Zhang
authors: Xin-Yuan
authors: XY
authors: Liu
authors: Yong-Zhi
authors: YZ
authors: Xue
mesh_terms: D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D008107:Liver Diseases / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D009163:Mycobacterium bovis; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013859:Thiocarbamates / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D019392:Cytochrome P-450 CYP2E1
keywords: Bacillus calmette Guérin; cytochrome P450 2E1; high-performance liquid chromatography; inducible nitric oxide synthase