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

Peroxisome proliferator-activated receptor alpha (PPARalpha) 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 PPARalpha 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.

Both PPARgamma and PPARdelta influence sulindac sulfide-mediated p21WAF1/CIP1 upregulation in a human prostate epithelial cell line.

Nonsteroidal anti-inflammatory drugs (NSAIDs) including sulindac sulfide are known to exert cancer chemopreventative activity in a range of cell lines. This activity has been shown to involve the upregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1. It is also known that NSAIDs can act as peroxisome proliferator-activated receptor (PPAR) agonists and antagonists.

Peroxisome proliferator activated receptor alpha regulates a male-specific cytochrome P450 in mouse liver.

We set out to find if the strain-specific, male-specific hepatic expression of Cyp4a protein in mouse was due to expression of Cyp4a12 and to understand the genetic basis for reported differences in expression. 12-Lauric acid hydroxylase (LAH) activity was found to show higher levels in male ddY, but not C57Bl/6, mouse liver microsomes. The expression of Cyp4a12 mRNA was studied using RNAase protection assays in male and female liver and kidney of nine mouse strains.

The effects of haloalkene cysteine conjugates on cytosolic free calcium levels in LLC-PK(1) cells--studies utilising digital imaging fluorescence microscopy.

The aim of this study was to examine the effect of haloalkene S-cysteine conjugates on cytosolic free Ca(2+) levels in renal epithelial cells using digital imaging fluorescence microscopy (DIFM). S-(1,2,3,4,4-pentachloro-1,3,-butadienyl)-L-cysteine (PCBC) and S-(1,2-dichlorovinyl)-L-cysteine (DCVC) were both cytotoxic to LLC-PK(1) cells in culture. Prior treatment of the cells with aminooxyacetic acid (AOAA), an inhibitor of the enzyme cysteine conjugate beta-lyase, afforded complete protection against the toxicity at concentrations of PCBC up to 100 microM and DCVC up to 500 microM.