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

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


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

Publisher: Oxford University Press
Year: 2008
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Provided by: Nottingham ePrints

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