Disease relevance of Pirinixic acid

• At 54 wk, the yield of hepatic neoplasms per liver was higher in rats fed WY-14,643 than in rats fed phenobarbital [1].
• Feeding a bile acid-enriched diet significantly reduced the degree of hepatomegaly and induction of target genes encoding enzymes of fatty acid beta-oxidation caused by treatment with the potent PPARalpha ligand Wyeth-14,643 [2].
• The PPAR-alpha ligand pirinixic acid (WY14643) functionally promoted IFN-gamma-induced ICAM-1 expression in normoxic epithelia, and this response was lost in cells pre-exposed to ambient hypoxia [3].
• The PPARalpha agonist WY14643 was administered (50 mg kg(-1) body weight intraperitoneally) 24 h before sampling [4].
• This study investigated the effects of the selective peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist WY14643 on ischemia/reperfusion (I/R) injury in the rat hippocampus [5].

High impact information on Pirinixic acid

• Furthermore, PPARalpha-null mice are resistant to hepatocarcinogenesis when fed a diet containing a potent nongenotoxic carcinogen WY-14,643 [6].
• In primary human monocytes and macrophages, the lipopolysaccharide- or interleukin-1ss-mediated induction of TF activity was also inhibited by fenofibric acid, WY14643, or GW2331 [7].
• Pretreatment of monocytes with WY14643 inhibited LPS-induced TF protein and mRNA expression without altering mRNA half-life [8].
• Peroxisome proliferators such as clofibric acid, nafenopin, and WY-14,643 have been shown to activate PPAR (peroxisome proliferator-activated receptor), a member of the steroid nuclear receptor superfamily [9].
• To test this hypothesis, mice were treated with a known rodent carcinogen and peroxisome proliferator, WY-14,643 (500 ppm, 1 month) [10].

Chemical compound and disease context of Pirinixic acid

• To examine the role of stimulated FAO during ischemia, Etomoxir (Eto), clofibrate, and WY-14,643 compounds were given 5 days prior to the induction of ischemia/reperfusion (I/R) injury [11].
• Since increased cell replication is associated with hepatic cancer caused by WY-14,643, glycine may have anti-cancer properties [12].
• To elucidate the mechanisms underlying the cholesterol lowering effects of PPARalpha agonists we investigated key regulators of cholesterol synthesis and uptake in rats and in the rat hepatoma cell line Fao after treatment with the PPARalpha agonists clofibrate and WY 14,643, respectively [13].
• In rat hepatoma (Fao) cells, treatment with WY-14,643 also increased the mRNA concentration of OCTN-2. mRNA concentrations of enzymes involved in carnitine biosynthesis were not altered by treatment with the PPARalpha agonists in livers of rats and in Fao cells [14].
• Some of the members of this class show evidence of genetic toxicity (most evidently the in vitro clastogen Wyeth 14,643, WY), while others do not (most evidently methyl clofenapate, MCP) [15].

Biological context of Pirinixic acid

• Fenofibric acid, WY14643, and GW2331 inhibited TF mRNA upregulation after stimulation of THP-1 cells with lipopolysaccharide or interleukin-1ss [7].
• This study demonstrates clearly that nafenopin and WY-14,643 activate Kupffer cell phagocytosis, suggesting a role for cell-to-cell communication in the stimulation of cell replication by peroxisome proliferators [16].
• Treatment of newborn mice with activators of peroxisome proliferator-activated receptors (PPARs), such as clofibrate, bezafibrate, or (4-chloro-6-(2,3-xylidine)-pirimidinylthio)acetic acid (WY 14,643), mimics the action of food intake on UCP-3 gene expression [17].
• WY14643 and PPARalpha target the S14 T3 regulatory region (TRR, -2.8 to -2.5 kilobases), a region containing 3 T3 response elements (TRE) [18].
• We propose that WY14643 protects the brain against excessive oxidative stress and inflammation and may thus be useful in treating stroke [5].

Anatomical context of Pirinixic acid

• Treatment of the recombinant cell line (ACOX::CAT) with peroxisome proliferators, WY 14,643, clofibrate, di(2-ethylhexyl) phtalhate, and acetylsalicylic acid resulted in differential increases of CAT protein 48 h after exposure [19].
• Both PPARalpha and the potent peroxisome proliferator, WY14643, inhibit S14CAT activity in transfected primary hepatocytes [18].
• The induction of UCP-3 gene expression by WY 14,643 is impaired in skeletal muscle of premature neonates, which do not express PPAR-alpha [17].
• The levels of S100B protein, a marker of cerebral injury used in stroke trials to monitor injury, were high in the hippocampus of rats exposed to I/R, but markedly reduced by WY14643 [5].
• Transient transfection experiments demonstrated that in contrast to the prototypic foreign chemical peroxisome proliferator pirinixic acid, DHEA-S and its 17 beta-reduced metabolite, 5-androstene-3 beta, 17 beta-diol-3 beta-sulfate, are inactive in mediating trans-activation by PPAR alpha in COS-1 cells [20].

Associations of Pirinixic acid with other chemical compounds

• Pioglitazone also repressed the SCD1 mRNA expression, whereas WY-14,643 had no apparent effect [21].
• However, in virgin mice, bezafibrate and WY-14,643 do not significantly affect UCP-3 mRNA expression, whereas troglitazone is at least as effective as it is in lactating dams [22].
• Constructs containing this element were transactivated by WY14643 and ciprofibrate, ligands of the peroxisome proliferator-activated receptor alpha (PPARalpha), in Caco2 cells [23].
• Like pioglitazone, WY14643 lowered basal plasma levels of glucose, triglycerides (-16% vs. untreated), and leptin (-52%), and also muscle triglyceride (-34%) and total long-chain acyl-CoAs (LCACoAs) (-41%) (P < 0.05) [24].
• The peroxisome proliferator-activated receptor (PPAR) alpha agonist WY 14,643 increased the secretion of apolipoprotein (apo) B-100, but not that of apoB-48, and decreased triglyceride biosynthesis and secretion from primary rat hepatocytes [25].

Gene context of Pirinixic acid

• Surprisingly, PPAR gamma and -delta are not activated by pirinixic acid (Wy 14,643), a potent peroxisome proliferator and activator of PPAR alpha [26].
• The specific ligand of PPAR-alpha WY 14,643 induces UCP-3 gene expression in a time- and dose-dependent manner, whereas the thiazolidinedione BRL 49653, specific for PPAR-gamma, has no effect [17].
• When HT-29 cells were incubated with TNF-alpha and WY14643, a further increase in COX-2 expression was detected [27].
• Moreover, the PPAR alpha agonist WY14643 inhibited macrophage differentiation and COX-2 gene expression [28].
• Stimulation of monocytes with LPS resulted in an 88% inhibition of PPAR-gamma mRNA expression that was fully restored by 15d-PGJ(2) but only to a partial extent by ciglitazone and WY-14,643 [29].

Analytical, diagnostic and therapeutic context of Pirinixic acid

• Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion: effects of the PPAR-alpha agonist WY14643 [5].
• To understand the molecular source of these radical species, NADPH oxidase-deficient (p47(phox)-null) and PPARalpha-null mice were examined after treatment with WY-14,643 [30].
• Feeding rats 0.1% WY-14,643 in the diet for 3 weeks, coupled with partial hepatectomy after 10 days, failed to initiate the development of growth-selectable foci identifiable by 3 enzyme histochemical stains [31].
• The analysis of detergent-extracted whole liver homogenates by immunoblotting showed a marked increase in the abundance of a 45-kDa variant of polymerase beta immunoreactivity and significant increases in the expression of Ref-1 and PCNA in WY 14,643-exposed rats [32].
• Treatment of cultured bovine aortic endothelial cells (BAECs) with PPARalpha ligands (fenofibrate and WY14643) remarkably upregulated LOX-1 expression, which was detected by western and northern blot analyses [33].

References