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

Al Kholaifi, Abdullah; Amer, Abeer; Jeffery, Brett; Gray, Tim J.B.; Roberts, Ruth A.; Bell, David Robert

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.

Citation

Al Kholaifi, A., Amer, A., Jeffery, B., Gray, T. J., Roberts, R. A., & Bell, D. R. (2008). Species-specific kinetics and zonation of hepatic DNA synthesis induced by ligands of PPARα. Toxicological Sciences, 104(1), https://doi.org/10.1093/toxsci/kfn062

• Journal Article Type: Article
• Publication Date: Jul 1, 2008
• Deposit Date: Oct 28, 2009
• Publicly Available Date: Oct 28, 2009
• Journal: Toxicological Sciences
• Print ISSN: 1096-6080
• Electronic ISSN: 1096-0929
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 104
• Issue: 1
• DOI: https://doi.org/10.1093/toxsci/kfn062
• Public URL: https://nottingham-repository.worktribe.com/output/1015197
• Publisher URL: http://toxsci.oxfordjournals.org/cgi/content/abstract/kfn062?ijkey=Q20yD42ARVr32gj&keytype=ref
• 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.