Proliferator Perfluorodecanoic Acid Research Articles

Peroxisome proliferator perfluorodecanoic acid alters glutathione and related enzymes.

Previously we have shown that treatment with the peroxisome proliferator perfluorodecanoic acid (PFDA) significantly increased hepatic reduced glutathione (GSH) content without altering the activity of selenium-glutathione peroxidase. In this study we examined some potential mechanisms by which PFDA treatment increases GSH levels. Male Sprague-Dawley rats were given a single injection of 0, 8.8, 17.5, and 35 mg PFDA in corn oil per kg body weight. Twelve days later the effects of PFDA on the activities of enzymes associated with GSH synthesis, utilization, and regeneration were assessed. The results showed that in a dose-dependent manner, PFDA treatment significantly decreased the activity of gamma-glutamylcysteine synthetase, while the activities of NADPH-generating enzymes, malic enzyme, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase were increased. PFDA treatment also dose dependently decreased cytosolic, but not microsomal, glutathione S-transferase activity, and the activity of glutathione reductase was decreased by the highest dose of PFDA. The data obtained suggest that increased hepatic GSH levels following PFDA treatment may result from increased regeneration and/or decreased utilization.

Regulation of Peroxisome Proliferator-Activated Receptor-α mRNA in Rat Liver

Chemical-induced peroxisome proliferation in rodent liver is postulated to occur via activation of members of the steroid hormone receptor superfamily, the peroxisome proliferator-activated receptors (PPARs). In the present study, the expression of the predominant liver subtype PPARα was examined and compared to that of acyl-CoA oxidase (ACO), a marker for peroxisome proliferation and a prototype for genes regulated via PPARs. Despite the induction of both mRNA speciesin vivoby the peroxisome proliferator perfluorodecanoic acid (PFDA), dose response and time course indicate PPARα and ACO are not controlled similarly. Messenger RNA levels for ACO increased rapidly in rat liver and declined over the subsequent 7 days following PFDA administration, while PPARα mRNA increased slower and remained elevated over this period. In addition, PPARα mRNA accumulation in PFDA-treated rats appears to be due primarily to hypophagia as pair feeding and complete caloric restriction result in a large increase in the concentration of this messenger RNA. Nuclear run-on experimentsin vivosuggest that, unlike ACO, PFDA as well as caloric restriction results in accumulation of PPARα mRNA which cannot be explained solely by transcriptional activation. These data indicate that PPARα mRNA accumulation has a very small peroxisome proliferator-dependent component and that other factors may be involved. A rat hepatoma cell line was examined to determine the direct effect of peroxisome proliferators on PPARα mRNA. PPARα and ACO mRNA levels were increased rapidly in the rat hepatoma cell line FaO after treatment with PFDA or the prototypical peroxisome proliferator Wy 14,643. In this cell line, PPARα mRNA levels are not affected by glucagon or insulin and in addition to peroxisome proliferators are induced in this cell line by oleic acid and dexamethasone. The latter treatment had the greatest effect on PPARα mRNA accumulation while having a minimal effect on ACO mRNA. Treatment of FaO cells with actinomycin D prior to Wy 14,643 abolished ACO and PPARα mRNA accumulation, demonstrating that there must be a transcriptional component of the peroxisome proliferator response. Therefore, although PPARα is responsive to peroxisome proliferators and direct effects are observed in cell culture, mRNA accumulationin vivois predominantly posttranscriptional, and endogenous regulators such as glucocorticoids may play critical roles in the tissue- and developmentally specific expression of this steroid hormone receptor.

AIDS and stressors I: Worldwide rice of immunological stressors

Acyl-CoA binding protein (ACBP) and fatty acid binding protein (FABP) are important intracellular lipid binding proteins. The purpose of the present experiments was to test the hypothesis that peroxisome proliferators induce ACBP in rat hepatocytes as has been shown previously for FABP. The effects of two structurally dissimilar peroxisome proliferators perfluorodecanoic acid (PFDA) and clofibric acid (CPIB) were examined in primary rat hepatocyte cultures in a chemically defined media. Both compounds alter lipid metabolism in primary rat hepatocytes in a similar fashion, although PFDA is more potent than CPIB at inducing peroxisomal β-oxidation. In addition, PFDA and CPIB compete with long-chain fatty acids for binding to FABP but do not compete with long-chain acyl-CoA esters for binding to ACBP. The concentration of ACBP and FABP was increased in peroxisome proliferator-treated hepatocytes relative to vehicle controls within 48 h of treatment. Evidence is given to support increases in ACBP and FABP mRNA being the cause of the increased protein levels by peroxisome proliferators. In addition, the peroxisome proliferators PFDA, perfluorooctanoic acid and ciprofibrate induced hepatic ACBP following in vivo administration to rats indicating that this phenomena is not exclusive to in vitro systems. Therefore, ACBP appears to be a member of the peroxisome proliferator loci, a group of lipid metabolizing proteins, including FABP, which are regulated by peroxisome proliferators such as fibric acids and perfluorinated fatty acids.

Molecular Changes in Rat Pancreas Following Exposure to Fenofibrate or Ciprofibrate

Acyl-CoA binding protein (ACBP) and fatty acid binding protein (FABP) are important intracellular lipid binding proteins. The purpose of the present experiments was to test the hypothesis that peroxisome proliferators induce ACBP in rat hepatocytes as has been shown previously for FABP. The effects of two structurally dissimilar peroxisome proliferators perfluorodecanoic acid (PFDA) and clofibric acid (CPIB) were examined in primary rat hepatocyte cultures in a chemically defined media. Both compounds alter lipid metabolism in primary rat hepatocytes in a similar fashion, although PFDA is more potent than CPIB at inducing peroxisomal β-oxidation. In addition, PFDA and CPIB compete with long-chain fatty acids for binding to FABP but do not compete with long-chain acyl-CoA esters for binding to ACBP. The concentration of ACBP and FABP was increased in peroxisome proliferator-treated hepatocytes relative to vehicle controls within 48 h of treatment. Evidence is given to support increases in ACBP and FABP mRNA being the cause of the increased protein levels by peroxisome proliferators. In addition, the peroxisome proliferators PFDA, perfluorooctanoic acid and ciprofibrate induced hepatic ACBP following in vivo administration to rats indicating that this phenomena is not exclusive to in vitro systems. Therefore, ACBP appears to be a member of the peroxisome proliferator loci, a group of lipid metabolizing proteins, including FABP, which are regulated by peroxisome proliferators such as fibric acids and perfluorinated fatty acids.

Induction of hepatic acyl-CoA-binding protein and liver fatty acid-binding protein by perfluorodecanoic acid in rats: Lack of correlation with hepatic long-chain acyl-CoA levels

Liver fatty acid-binding protein (L-FABP) and acyl-CoA-binding protein (ACBP) are involved in the intracellular trafficking and compartmentalization of fatty acids and fatty acyl-CoA esters, respectively, in the liver. Both proteins are induced in rat liver by the potent peroxisome proliferator perfluorodecanoic acid (PFDA). While it is believed that the peroxisome proliferator-activated receptor may mediate the responses to peroxisome proliferators by inducing responsive genes, the ligand(s) of this receptor remains unknown. We hypothesized that induction of L-FABP and ACBP in rat liver by PFDA is secondary to accumulation of long-chain acyl-CoA esters. However, neither dose-response nor time-course effects of PFDA on hepatic long-chain acyl-CoA, L-FABP, or ACBP concentrations confirmed this hypothesis. In a dose-response study, PFDA increased hepatic long-chain acyl-CoA concentrations (7 days after treatment) over the dose range of 20–50 mg/kg, whereas it increased ACBP and L-FABP over the wider dose range of 20–65 mg/kg. In the time-course study, PFDA treatment (50 mg/kg) elevated long-chain acyl-CoA esters in the liver beginning on day 3 post-treatment, yet hepatic L-FABP concentrations were increased earlier beginning on day 2 and ACBP was not induced until day 7. To determine if this dissociation of increases in hepatic long-chain acyl-CoA concentrations from increases in hepatic L-FABP and ACBP concentrations could be demonstrated under other conditions, control rats fasted for 24–48 hr were used. Fasting increased hepatic long-chain acyl-CoA levels to a greater extent than PFDA treatment, yet neither L-FABP nor ACBP was induced. We conclude that elevated concentrations of hepatic long-chain acyl-CoAs in PFDA-treated rats are not a major contributor to the induction of L-FABP or ACBP by peroxisome proliferators. A more plausible mechanism is that PFDA induces L-FABP and ACBP by activating the peroxisome proliferator receptor directly rather than indirectly through long-chain acyl-CoA esters.

Effect of the peroxisome proliferator perfluorodecanoic acid on the promotion of two-stage hepatocarcinogenesis in rats

This study was conducted to determine if the peroxisome proliferator perfluorodecanoic acid (PFDA) has promoting activity in two-stage hepatocarcinogenesis. Because PFDA is a non-competitive inhibitor of the peroxisomal bifunctional enzyme and thus inhibits the peroxisomal β pathway, we hypothesized that PFDA may not have promoting activity as do other peroxisome proliferators, because hydrogen peroxide production is inhibited. Twenty-four hours after partial hepatectomy, female Sprague-Dawley rats were given an initiating dose of 10 mg/kg diethylnitrosamine by gavage. The rats were divided into five groups that received monthly i.p. injections of 0.0, 0.05, 0.50 or 5.0 mg/kg PFDA in corn oil or were placed on diets that contained either 0.01% ciprofibrate or 0.05% phenobarbital for 9 or 18 months. Both ciprofibrate and the highest dose of PFDA increased the activity of the peroxisomal enzyme fatty acyl CoA oxidase. PFDA treatment did not increase the tumor incidence or the number of altered hepatic foci at 9 or 18 months, although the mean volume of foci was increased at 9 months. Ciprofibrate increased the incidence of hepatocellular carcinomas at 18 months but did not increase the number or volume of altered hepatic foci at 9 or 18 months. Phenobarbital increased the number and volume of foci but did not influence the tumor incidence. The results of this investigation indicate that PFDA is not a promoter of hepatocarcinogenesis.

Coordinate induction of acyl-CoA binding protein, fatty acid binding protein and peroxisomal β-oxidation by peroxisome proliferators

Acyl-CoA binding protein (ACBP) and fatty acid binding protein (FABP) are important intracellular lipid binding proteins. The purpose of the present experiments was to test the hypothesis that peroxisome proliferators induce ACBP in rat hepatocytes as has been shown previously for FABP. The effects of two structurally dissimilar peroxisome proliferators perfluorodecanoic acid (PFDA) and clofibric acid (CPIB) were examined in primary rat hepatocyte cultures in a chemically defined media. Both compounds alter lipid metabolism in primary rat hepatocytes in a similar fashion, although PFDA is more potent than CPIB at inducing peroxisomal β-oxidation. In addition, PFDA and CPIB compete with long-chain fatty acids for binding to FABP but do not compete with long-chain acyl-CoA esters for binding to ACBP. The concentration of ACBP and FABP was increased in peroxisome proliferator-treated hepatocytes relative to vehicle controls within 48 h of treatment. Evidence is given to support increases in ACBP and FABP mRNA being the cause of the increased protein levels by peroxisome proliferators. In addition, the peroxisome proliferators PFDA, perfluorooctanoic acid and ciprofibrate induced hepatic ACBP following in vivo administration to rats indicating that this phenomena is not exclusive to in vitro systems. Therefore, ACBP appears to be a member of the peroxisome proliferator loci, a group of lipid metabolizing proteins, including FABP, which are regulated by peroxisome proliferators such as fibric acids and perfluorinated fatty acids.