title: Hepatic expression of detoxification enzymes is decreased in human obstructive cholestasis due to gallstone biliary obstruction.
abstract: OBJECTIVE
  Levels of bile acid metabolic enzymes and membrane transporters have been reported to change in cholestasis. These alterations (e.g. CYP7A1 repression and MRP4 induction) are thought to be adaptive responses that attenuate cholestatic liver injury. However, the molecular mechanisms of these adaptive responses in human obstructive cholestasis due to gallstone biliary obstruction remain unclear.
  
  
  METHODS
  We collected liver samples from cholestatic patients with biliary obstruction due to gallstones and from control patients without liver disease (n = 22 per group). The expression levels of bile acid synthetic and detoxification enzymes, membrane transporters, and the related nuclear receptors and transcriptional factors were measured.
  
  
  RESULTS
  The levels of bile acid synthetic enzymes, CYP7B1 and CYP8B1, and the detoxification enzyme CYP2B6 were increased in cholestatic livers by 2.4-fold, 2.8-fold, and 1.9-fold, respectively (p<0.05). Conversely, the expression levels of liver detoxification enzymes, UGT2B4/7, SULT2A1, GSTA1-4, and GSTM1-4, were reduced by approximately 50% (p<0.05) in human obstructive cholestasis. The levels of membrane transporters, OSTβ and OCT1, were increased 10.4-fold and 1.8-fold, respectively, (p<0.05), whereas those of OSTα, ABCG2 and ABCG8 were all decreased by approximately 40%, (p<0.05) in human cholestatic livers. Hepatic nuclear receptors, VDR, HNF4α, RXRα and RARα, were induced (approximately 2.0-fold, (p<0.05) whereas FXR levels were markedly reduced to 44% of control, (p<0.05) in human obstructive cholestasis. There was a significantly positive correlation between the reduction in FXR mRNA and UGT2B4/7, SULT2A1, GSTA1, ABCG2/8 mRNA levels in livers of obstructive cholestatic patients (p<0.05).
  
  
  CONCLUSIONS
  The levels of hepatic detoxification enzymes were significantly decreased in human obstructive cholestasis, and these decreases were positively associated with a marked reduction of FXR levels. These findings are consistent with impaired detoxification ability in human obstructive cholestasis.
authors: Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, P.R. China.
authors: Jin
authors: J
authors: Chai
authors: Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, P.R. China.
authors: Xinchan
authors: X
authors: Feng
authors: Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, P.R. China.
authors: Liangjun
authors: L
authors: Zhang
authors: Department of Pediatrics, Southwest Hospital, Third Military Medical University, Chongqing, P.R. China.
authors: Sheng
authors: S
authors: Chen
authors: Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, P.R. China.
authors: Ying
authors: Y
authors: Cheng
authors: School of Nursing, Third Military Medical University, Chongqing, P.R. China.
authors: Xiaochong
authors: X
authors: He
authors: Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China.
authors: Yingxue
authors: Y
authors: Yang
authors: Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, P.R. China.
authors: Yu
authors: Y
authors: He
authors: Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, P.R. China.
authors: Huaizhi
authors: H
authors: Wang
authors: Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, P.R. China.
authors: Rongquan
authors: R
authors: Wang
authors: Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, P.R. China.
authors: Wensheng
authors: W
authors: Chen
mesh_terms: D002779:Cholestasis / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D042882:Gallstones / Q000150:complications*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008099:Liver / Q000201:enzymology*; D026901:Membrane Transport Proteins / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation
chemical_list: D026901:Membrane Transport Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors