title: The effect of benzo[a]pyrene on metabolic activation of anticancer drug ellipticine in mice.
abstract: OBJECTIVE
  The aim of this study was to investigate a role of cytochrome P450 (CYP) and peroxidase in ellipticine oxidative activation in two mouse strains differing in expression of NADPH:CYP reductase (POR) [the HRN (Hepatic Cytochrome P450 Reductase Null) mice, in which POR is deleted in hepatocytes and its wild-type (WT) counterpart], and in levels of CYP1A1/2 and cytochrome b5 that were modulated by treatment of these mouse models with a CYP1A inducer, benzo[a]pyrene (BaP).
  
  
  METHODS
  Ellipticine-DNA adducts were detected by 32P-postlabeling. HPLC was employed for the separation and characterization of ellipticine metabolites.
  
  
  RESULTS
  Hepatic microsomes of HRN and WT mice activate ellipticine to form ellipticine-derived DNA adducts. A 2.2- and 10.4-fold increase in amounts of ellipticine-derived DNA adducts formed by liver microsomes was caused by exposure of HRN and WT mice to BaP, respectively. The results found and utilization of NADPH and arachidonic acid, cofactors of CYP- and cyclooxygenase (COX)-dependent enzyme systems, respectively, as well as inhibitors of CYP1A1/2 and 3A, demonstrate that the CYP1A and 3A enzymes play a major role in ellipticine activation in liver microsomes. In addition, the COX enzyme is important in ellipticine activation in liver of HRN mice.
  
  
  CONCLUSIONS
  The CYP1A and 3A enzymes activate ellipticine mainly in liver of WT mice, whereas peroxidase COX plays this role in liver of HRN mice. Treatment of mice with BaP increases an impact of CYP1A on ellipticine activation. A pattern of expression levels of these enzymes plays a crucial role in their impact on this process.
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic. stiborov@natur.cuni.cz.
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborova
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.
authors.forename: Vera
authors.initials: V
authors.lastname: Cerna
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Moserova
authors.affiliation: Analytical and Environmental Sciences Division, King's College London, MRC-PHE Centre for Environmental and Health, London, UK.
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
authors.affiliation: Division of Preventive Oncology, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Frei
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D001711:Biotransformation / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004611:Ellipticines / Q000493:pharmacokinetics*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004611:Ellipticines; C034192:ellipticine; D001564:Benzo(a)pyrene; D003577:Cytochrome P-450 Enzyme System; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2