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

PPARα ligands evoke a profound mitogenic response in rodent liver, and the aim of this studywas 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 in129S4/SvJae mice, but the potent PPARα ligand, ciprofibrate, induced hepatocyte DNA synthesisonly after 3 or 4 days dosing; higher or lower doses did not hasten the DNA synthesisresponse. This contrasted with the rapid induction (24 hours) reported by Styles et al. (Carcinogenesis9:1647-1655). C57BL/6 and DBA/2J mice showed significant induction of DNA synthesisafter 4, but not 2, days ciprofibrate treatment. Alderley Park and 129S4/SvJae mice dosedwith 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 orPPARα 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 inducedat 24 hours after dosing, with a second peak at 48 hours. Lobular localisation of hepatocyteDNA synthesis showed preferential periportal induction of DNA synthesis in rat, butpanlobular zonation of hepatocyte DNA synthesis in mouse. These results characterise a markedlylater hepatic induction of panlobular DNA synthesis by PPARα ligands in mouse, comparedto rapid induction of periportal DNA synthesis in rat