title: Effect of erythropoietin on hepatic cytochrome P450 expression and function in an adenine-fed rat model of chronic kidney disease.
abstract: OBJECTIVE
  Erythropoietin (EPO) is used to treat anaemia associated with chronic kidney disease (CKD). Hypoxia is associated with anaemia and is known to cause a decrease in cytochrome P450 (P450) expression. As EPO production is regulated by hypoxia, we investigated the role of EPO on P450 expression and function.
  
  
  METHODS
  Male Wistar rats were subjected to a 0.7% adenine diet for 4 weeks to induce CKD. The diet continued for an additional 2 weeks while rats received EPO by i.p. injection every other day. Following euthanasia, hepatic P450 mRNA and protein expression were determined. Hepatic enzyme activity of selected P450s was determined and chromatin immunoprecipitation was used to characterize binding of nuclear receptors involved in the transcriptional regulation of CYP2C and CYP3A.
  
  
  RESULTS
  EPO administration decreased hepatic mRNA and protein expression of CYP3A2 (P < 0.05), but not CYP2C11. Similarly, EPO administration decreased CYP3A2 protein expression by 81% (P < 0.001). A 32% decrease (P < 0.05) in hepatic CYP3A enzymatic activity (Vmax ) was observed for the formation of 6βOH-testosterone in the EPO-treated group. Decreases in RNA pol II recruitment (P < 0.01), hepatocyte nuclear factor 4α binding (P < 0.05) and pregnane X receptor binding (P < 0.01) to the promoter region of CYP3A were also observed in EPO-treated rats.
  
  
  CONCLUSIONS
  Our data show that EPO decreases the expression and function of CYP3A, but not CYP2C in rat liver.
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, ON, Canada.
authors.forename: D A
authors.initials: DA
authors.lastname: Feere
authors.forename: T J
authors.initials: TJ
authors.lastname: Velenosi
authors.forename: B L
authors.initials: BL
authors.lastname: Urquhart
mesh_terms: D000225:Adenine; D000818:Animals; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004032:Diet; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000494:pharmacology*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D000077297:Pregnane X Receptor; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology
chemical_list: D000090702:Constitutive Androstane Receptor; D051557:Hepatocyte Nuclear Factor 4; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011994:Recombinant Proteins; D004921:Erythropoietin; D003577:Cytochrome P-450 Enzyme System; D012319:RNA Polymerase II; D000225:Adenine