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ToxSci Advance Access originally published online on March 28, 2008
Toxicological Sciences 2008 104(1):74-85; doi:10.1093/toxsci/kfn062
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Species-Specific Kinetics and Zonation of Hepatic DNA Synthesis Induced by Ligands of PPAR{alpha}

Abdullah Al Kholaifi*, Abeer Amer*, Brett Jeffery*, Tim J. B. Gray{dagger}, Ruth A. Roberts{ddagger} and David R. Bell*,1

* School of Biology, University of Nottingham, University Park, Nottingham NG7 2RD, UK {dagger} Sanofi-Aventis, Willowburn Avenue, Alnwick, Northumberland NE66 2JH, UK {ddagger} AstraZeneca Pharmaceuticals plc, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK

1 To whom correspondence should be addressed. Fax: +44-115-9513251. E-mail david.bell{at}nottingham.ac.uk.

Received February 13, 2008; accepted March 14, 2008


  Abstract

Peroxisome proliferator–activated receptor {alpha} (PPAR{alpha}) ligands evoke a profound mitogenic response in rodent liver, and the aim of this study was to characterize the kinetics of induction of DNA synthesis. The CAR ligand, 1,4-bis[2-(3,5-dichoropyridyloxy)]benzene, caused induction of hepatocyte DNA synthesis within 48 h in 129S4/SvJae mice, but the potent PPAR{alpha} ligand, ciprofibrate, induced hepatocyte DNA synthesis only after 3 or 4 days dosing; higher or lower doses did not hasten the DNA synthesis response. This contrasted with the rapid induction (24 h) reported by Styles et al., 1988, Carcinogenesis 9, 1647–1655. C57BL/6 and DBA/2J mice showed significant induction of DNA synthesis after 4, but not 2, days ciprofibrate treatment. Alderley Park and 129S4/SvJae mice dosed with methylclofenapate induced hepatocyte DNA synthesis at 4, but not 2, days after dosing and proved that inconsistency with prior work was not due to a difference in mouse strain or PPAR{alpha} ligand. Ciprofibrate-induced liver DNA synthesis and growth was absent in PPAR{alpha}-null mice and are PPAR{alpha} dependent. In the Fisher344 rat, hepatocyte DNA synthesis was induced at 24 h after dosing, with a second peak at 48 h. Lobular localization of hepatocyte DNA synthesis showed preferential periportal induction of DNA synthesis in rat but panlobular zonation of hepatocyte DNA synthesis in mouse. These results characterize a markedly later hepatic induction of panlobular DNA synthesis by PPAR{alpha} ligands in mouse, compared to rapid induction of periportal DNA synthesis in rat.

Key Words: liver growth; hepatocyte; PPAR; peroxisome proliferation; DNA synthesis.


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