title: Down-regulation of hepatic CYP3A in chronic renal insufficiency.
abstract: OBJECTIVE
  The objective of this study was to investigate the mechanisms underlying the decrease in hepatic clearance of some drugs metabolized by CYP450 enzymes in chronic renal insufficiency (CRI).
  
  
  METHODS
  CRI was induced in male Sprague-Dawley rats (n = 7) by the remnant kidney model (RKM); control animals (C) (n = 12) underwent sham surgery, of which n = 6 rats were pair-fed (CPF) with CRI rats and others (n = 6) had free access to food. Serum creatinine (Scr) and urea nitrogen (SUN) were monitored every 2 weeks. On day 36, livers were isolated, and microsomes were prepared. Catalytic activities were measured through O-demethylation (CYP2D) and N-demethylation of dextromethorphan (CYP3A) and O-deethylation of 7-ethoxyresorufin (CYP1A2). CYP450 protein and mRNA levels were also measured.
  
  
  RESULTS
  Compared with CPF, Scr and SUN levels in CRI rats were increased twofold (p < 0.01) and 2.5-fold (p < 0.01), respectively. No effect on CYP1A2 and CYP2D activities, mRNA, or protein levels was observed between the groups. There was a reduction (41.8 +/- 20%, p < 0.01) in CYP3A activity, mRNA (p < 0.05), and protein levels (p < 0.05) in CRI rats compared to CPF.
  
  
  CONCLUSIONS
  CRI induced by RKM does not have an effect on hepatic CYP1A2 and CYP2D enzymes but does reduce CYP3A activity, probably through down-regulation of CYP3A2.
authors: Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Bhaskar
authors: B
authors: Rege
authors: Richard
authors: R
authors: Krieg
authors: Ning
authors: N
authors: Gao
authors: Mohamadi A
authors: MA
authors: Sarkar
mesh_terms: D000429:Alcohol Oxidoreductases; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000378:metabolism; D015153:Blotting, Western; D002384:Catalysis; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D004195:Disease Models, Animal; D015536:Down-Regulation; D007527:Isoenzymes / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D000429:Alcohol Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; C504568:Cyp2d1 protein, rat; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D010089:Oxidoreductases, N-Demethylating