DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on June 8, 2006; DOI: 10.1124/dmd.106.009670

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.106.009670v1
34/9/1556    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Donato, M. T.
Right arrow Articles by Gomez-Lechon, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Donato, M. T.
Right arrow Articles by Gomez-Lechon, M. J.


Received for publication February 7, 2006.
Revised June 8, 2006.
Accepted for publication June 8, 2006.

POTENTIAL IMPACT OF STEATOSIS ON P450 ENZYMES OF HUMAN HEPATOCYTES ISOLATED FROM FATTY LIVER GRAFTS

Maria Teresa Donato 1*, Agustin Lahoz 2, Nuria Jimenez 1, Gabriela Perez 1, Alfonso Serralta 1, Jose Mir 1, Jose V. Castell 1, Maria Jose Gomez-Lechon 1

1 Hospital La Fe 2 Advancell

* Address correspondence to: E-mail: donato_mte{at}gva.es

Abstract

Liver grafts discarded for transplantation because of macrosteatosis can constitute a valuable source of human hepatocytes for in vitro metabolic and pharmaco-toxicological studies or for therapeutic applications. A condition for using hepatocyte suspensions for these purposes is the preservation of their metabolic competence and, particularly, drug-metabolising enzymes. A reduction in microsomal cytochrome P450 (P450) activities was observed in fatty livers (> 40% steatosis) with respect to normal tissue. Similarly, decreased levels of 7-ethoxycoumarin O-deethylation and testosterone metabolism were observed in human hepatocyte cultures prepared from steatotic liver tissue. To clarify the potential impact of lipid accumulation on human hepatic P450 enzymes, we have used an in vitro model of "cellular steatosis" by incubation of cultured hepatocytes with increasing concentrations (0.25-3 mM) of long chain free fatty acids (FFA). A dose-dependent accumulation of lipids in the cytosol is induced by FFA mixture. Hepatocytes exposed to 1 mM FFA for 14 h showed lower activity values of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 enzymes than non-treated hepatocytes (about 45-65% reduction). This treatment also produced significant decreases in CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 mRNAs to about 55-75% of mRNA levels in control cells. Our results suggest that, although human hepatocytes isolated from steatotic liver show reduced P450 activities, they are metabolically competent and can be used for drug metabolism studies.


Key words: CYP expression, cytochrome P450 catalyzed oxidations, cytochrome P450 function, hepatocytes, human CYP enzymes


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
W. V. Zhang, I. Ramzan, and M. Murray
Impaired Microsomal Oxidation of the Atypical Antipsychotic Agent Clozapine in Hepatic Steatosis
J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 770 - 777.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.