title: Expression of cytochrome P450 2C and 3A in female rat liver after long-term administration of gonadoliberin analogs.
abstract: OBJECTIVE
  Gonadoliberin (GnRH) analogs may be expected to indirectly modify growth hormone (GH) total concentration and its 24-h secretion profile. As a consequence, changes in the levels of GH may modify the mechanism of sex-dependent cytochromes P450 (CYP450) synthesis, including the expression of transcriptional factors. The aim of the study has been to evaluate the effect of long-term administration of a low dose of GnRH analogs on hepatic expression of CYP2C and CYP3A isoforms, and the transcription factors: pregnane X receptor (PXR), hepatocyte nuclear factor 4α (HNF4α), HNF6 and signal transducers and activators of transcription 5b (STAT5b).
  
  
  METHODS
  The study was carried out on adult female Sprague-Dawley rats during a 3-month treatment with dalarelin (GnRH agonist) and cetrorelix (GnRH antagonist), at a daily intraperitoneal injection (i.p.) dose of 6 μg/kg body weight/day, and 1, 2, and 4 weeks after treatment discontinuation. The concentrations of ovarian hormones and GH in the blood serum were determined by radioimmunoassay and enzyme-linked immunosorbent assay (ELISA) method, respectively. Then, the expression of hepatic CYP450s (reverse transcription polymerase chain reaction - RT-PCR, Western blot and immunohistochemistry) and transcription factors (RT-PCR) was evaluated.
  
  
  RESULTS
  We have found that cetrorelix induces changes in the circadian pattern of GH secretion and enhances GH blood concentrations. These changes may cause increased expression of both, female-specific CYP450s (especially CYP3A9), and HNF4α/HNF6 transcription factors. Decrease in GH blood concentrations, resulting from the effect of dalarelin, may promote inhibition of female-specific CYP2C12 and CYP3A9 isoforms as well as STAT5b transcription factor. Slight changes in sex-independent CYP3A1 protein expression caused by GnRH analogs were also observed.
  
  
  CONCLUSIONS
  In adult female rats, HNF4α/HNF6 and STAT5b seem to be crucial for the regulation of GnRH antagonist/GH- and GnRH agonist/GH-dependent pattern of CYP450 expression, respectively.
authors.affiliation: Medical University of Silesia, Katowice, Poland (School of Medicine in Katowice, Chair of Histology and Embryology, Department of Cytophysiology).
authors.forename: Rafał
authors.initials: R
authors.lastname: Skowronek
authors.affiliation: Medical University of Silesia, Katowice, Poland (School of Medicine in Katowice, Chair of Histology and Embryology, Department of Cytophysiology). pcz@sum.edu.pl.
authors.forename: Piotr
authors.initials: P
authors.lastname: Czekaj
authors.affiliation: Medical University of Silesia, Katowice, Poland (School of Medicine in Katowice, Chair of Histology and Embryology, Department of Histology).
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Suszka-Świtek
authors.affiliation: Medical University of Silesia, Katowice, Poland (School of Medicine in Katowice, Chair of Histology and Embryology, Department of Histology).
authors.forename: Ewa
authors.initials: E
authors.lastname: Czech
authors.affiliation: Medical University of Silesia, Katowice, Poland (School of Medicine in Katowice, Chair of Histology and Embryology, Department of Histology).
authors.forename: Anna
authors.initials: A
authors.lastname: Wiaderkiewicz
authors.affiliation: Medical University of Silesia, Katowice, Poland (School of Medicine in Katowice, Chair of Histology and Embryology, Department of Cytophysiology).
authors.forename: Danuta
authors.initials: D
authors.lastname: Plewka
authors.affiliation: Medical University of Silesia, Katowice, Poland (School of Medicine in Katowice, Chair of Histology and Embryology, Department of Cytophysiology).
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Bryzek
mesh_terms: D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004195:Disease Models, Animal; D005260:Female; D005500:Follow-Up Studies; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: C400322:cytochrome P-450 CYP2C subfamily; C404725:dalarelin; D007987:Gonadotropin-Releasing Hormone; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A
keywords: CYP2C; CYP3A; cetrorelix; dalarelin; growth hormone; liver-enriched transcription factors