Species-specific kinetics and zonation of hepatic DNA synthesis induced by ligands of PPARα

Al Kholaifi, Abdullah and Amer, Abeer and Jeffery, Brett and Gray, Tim J.B. and Roberts, Ruth A. and Bell, David Robert (2008) Species-specific kinetics and zonation of hepatic DNA synthesis induced by ligands of PPARα. Toxicological Sciences, 104 (1). pp. 74-85. ISSN 1096-6080

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Abstract

PPARα ligands evoke a profound mitogenic response in rodent liver, and the aim of this study

was to characterise 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 hours in

129S4/SvJae mice, but the potent PPARα 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 hours) reported by Styles et al. (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

PPARα ligand. Ciprofibrate-induced liver DNA synthesis and growth was absent in PPARα-

null mice, and are PPARα-dependent. In the Fisher344 rat, hepatocyte DNA synthesis was induced

at 24 hours after dosing, with a second peak at 48 hours. Lobular localisation of hepatocyte

DNA synthesis showed preferential periportal induction of DNA synthesis in rat, but

panlobular zonation of hepatocyte DNA synthesis in mouse. These results characterise a markedly

later hepatic induction of panlobular DNA synthesis by PPARα ligands in mouse, compared

to rapid induction of periportal DNA synthesis in rat.

Item Type: Article
Additional Information: This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Toxicological Sciences following peer review. The definitive publisher-authenticated version is available online at: http://toxsci.oxfordjournals.org/cgi/content/abstract/kfn062?ijkey=Q20yD42ARVr32gj&keytype=ref.
Schools/Departments: University of Nottingham UK Campus > Faculty of Medicine and Health Sciences > School of Life Sciences > School of Biology
Depositing User: Bell, Dr David R
Date Deposited: 28 Oct 2009 15:22
Last Modified: 29 Oct 2009 01:00
URI: http://eprints.nottingham.ac.uk/id/eprint/1068

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