gms | German Medical Science

27. Wissenschaftlicher Kongress der Deutschen Hochdruckliga

Deutsche Liga zur Bekämpfung des hohen Blutdrucks – Deutsche Hypertonie Gesellschaft e. V.

26. bis 29.11.2003, Bonn

Cooperation of rat renal CYP4A and CYP2C enzymes in the formation of secondary arachidonic acid metabolites

Interaktion von CYP4a und Cyp2C23 bei Bildung von sekundären Arachidonsäurmetabolite in der Rattenniere

Meeting Abstract (Hypertonie 2003)

  • presenting/speaker D.N. Müller - Franz-Volhard Klinik und Max-Delbrück Centrum, HELIOS Franz-Volhard Klinik (Berlin, D)
  • E. Barbosa-Sicard - Franz-Volhard Klinik und Max-Delbrück Centrum, HELIOS Franz-Volhard Klinik (Berlin, D)
  • M. Markovic - Franz-Volhard Klinik und Max-Delbrück Centrum, HELIOS Franz-Volhard Klinik (Berlin, D)
  • H. Honeck - Franz-Volhard Klinik und Max-Delbrück Centrum, HELIOS Franz-Volhard Klinik (Berlin, D)
  • E. Shagdarsuren - Franz-Volhard Klinik und Max-Delbrück Centrum, HELIOS Franz-Volhard Klinik (Berlin, D)
  • H. Hercule - Franz-Volhard Klinik und Max-Delbrück Centrum, HELIOS Franz-Volhard Klinik (Berlin, D)
  • F.C. Luft - Franz-Volhard Klinik und Max-Delbrück Centrum, HELIOS Franz-Volhard Klinik (Berlin, D)
  • W.H. Schunck - Franz-Volhard Klinik und Max-Delbrück Centrum, HELIOS Franz-Volhard Klinik (Berlin, D)

Hypertonie 2003. 27. Wissenschaftlicher Kongress der Deutschen Hochdruckliga. Bonn, 26.-29.11.2003. Düsseldorf, Köln: German Medical Science; 2004. Doc03hochP5

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/hoch2003/03hoch105.shtml

Veröffentlicht: 11. November 2004

© 2004 Müller et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Primary products of cytochrome P450 (CYP)-dependent arachidonic acid (AA) metabolism, such as 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs), contribute to the regulation of vascular tone and renal function. Secondary metabolites include hydroxy-EETs (HEETs), which act as high affinity PPARa ligands. In the present study, we showed that several recombinant CYP2C enzymes do not only function as AA but also as 20-HETE epoxygenases and that this capacity provides a novel pathway of HEET formation in the rat kidney. Renal microsomes were isolated from 7-week old male Sprague-Dawley (SD) and from fenofibrate-treated (30mg/kg/d for 3 weeks) SD rats. HEETs produced from radiolabeled AA, EETs and 20-HETE were analyzed by reverse-phase HPLC followed by normal-phase HPLC to resolve the regioisomers. Renal microsomes efficiently produced HEETs from both EETs and 20-HETE. Fenofibrate induced 20-HETE epoxygenase activity 3-fold and 11,12-EET hydroxylase activity about 2-fold. An antibody against CYP2C23 abolished conversion of 20-HETE to HEETs, indicating that CYP2C23 is the predominant 20-HETE epoxygenase in rat renal microsomes. Recombinant CYP2C23 and renal microsomes produced identical patterns of HEET regioisomers from 20-HETE (20,8,9-HEET and 20,14,15-HEET in a ratio of 9:1). 20,8,9-HEET was also the major secondary metabolite produced from AA by renal microsomes. Immunohistochemical analysis revealed a co-localization of CYP2C23 and CYP4A proteins in tubules of the outer medulla and in medullary rays. These results demonstrate the existence of two HEET-generating pathways: (1) CYP4A-dependent hydroxylation of AA followed by CYP2C23-dependent 20-HETE epoxygenation and (2) CYP2C23-dependent epoxygenation of AA followed by CYP4A-dependent EET hydroxylation. Given the ability of HEETs to activate PPARa, HEETs may be important for the regulation of lipid metabolism and control of inflammation in the kidney.