Effects of hypolipidemic drugs nafenopin and clofibrate on phenotypic expression and cell death (apoptosis) in altered foci of rat liver

Abstract

Phenotypically altered liver foci were produced in female Wistar rats by a single dose of N-nitrosomorpholine followed by promotion with phenobarbital (PB) for 20 or 28 weeks. Then treatment was changed to either hexachlorocyclohexane (HCH), or cyproterone acetate (CPA), or nafenopin (Naf) or clofibrate (Clof), two hypolipidemic drugs. Foci were identified by a positive reaction for gamma-glutamyl-transpeptidase (GGT) and other cytological markers. HCH and CPA could substitute for PB as foci promoters; in contrast, Naf and Clof decreased expression of GGT in foci resulting in a decline of number and area of detectable foci, effects particularly pronounced with Naf. Immunohistochemical investigations of serial sections revealed that Naf also reduced expression of the altered phenotype when cytochrome P450-PB and pyruvate kinase (type L) were used as foci markers, but not when glutathione-S-transferase B (GST-B) was used. Thus, the number of foci with enhanced GST-B did not decline significantly after the change from PB to Naf treatment. Furthermore, the reduction of GGT and the decrease of foci number during Naf treatment were not associated with increased evidence of cell death by apoptosis in foci, in contrast to the situation after PB withdrawal. These findings strongly suggest that the disappearance of GGT-positive foci after Naf is due to a phenotypic change resulting in a suppression of GGT expression rather than to physical elimination of foci.

Transcription Profiling Distinguishes Dose-Dependent Effects in the Livers of Rats Treated with Clofibrate

“…However these studies have either used different PP (6,41), or significantly different dosing regimens (14). Although no statistically significant effects on apoptosis as assessed by caspase-3 immunohistochemistry were seen in the present study, an analysis of the liver pathology data identified an increase in the number of apoptotic bodies primarily in the centrilobular area in the 800 mg/kg/day dose group (Figure 1).…”

“…Along with PP-mediated hepatocellular proliferation, suppression of apoptosis by PP both in vitro and in vivo has been reported (6,14,41). However these studies have either used different PP (6,41), or significantly different dosing regimens (14).…”

“…An induction of proliferation and a deregulation between hepatocellular proliferation and apoptosis both in vitro and in vivo has been reported by several investigators (6,14,27,41). The increased proliferation may be caused by PPmediated induction of nuclear factor kappa B (NF-κB) in Kupffer cells resulting in secretion of mitogenic stimuli (8,43,44).…”

Modes of Action and Species-Specific Effects of Di-(2-ethylhexyl)Phthalate in the Liver

“…In adult animals, apoptosis acts as a safeguard to prevent cells with damaged DNA from progressing to a tumor. Several studies have shown that agonists of PPARα, including DEHP, suppress rates of apoptosis in rat and mouse liver in vivo [105,106,31]. Thus, it was hypothesized that the cells that would normally be removed by apoptosis may then persist for further mitogenic stimulation by non-genotoxic carcinogens, giving rise to tumors.…”

Epigenetic Effects of Endocrine Disrupting Chemicals: Phthalates: Review

“…34 Pek çok çalışmada fare ve sıçan karaciğerinde PPAR-α agonistlerinin in vivo olarak apoptozu baskıladıkları belirlenmiş-tir. 35,36 Ftalatlara temas sonrası normal olarak apoptozla uzaklaştırılan hücrelerin mitojenik stimülasyonla canlı kaldığı ve bölündüğü rapor edilmiştir. PPAR-α agonistleriyle yapılan bir çalış-mada, yalnızca orta (50 haftalık) ve ileri yaşlarda (100 haftalık) olan hayvanların karaciğerlerinin bu etkiye hassas olduğu, genç hayvanların karaciğer-lerinde bu etkinin görülmediği bildirilmiştir.…”