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At least 19 recordsLinked to original sources

PubMed1990

Peroxisome proliferation and modulation of rat liver carcinogenesis by 2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, perfluorooctanoic acid and nafenopin.

Using an initiation--selection--promotion protocol for induction of liver tumors in Wistar rats, the modulating action of various peroxisome proliferators on neoplasia as well as on selected biochemical parameters was studied. After treatment with diethylnitrosamine (DEN), the animals were subsequently subjected to a selection procedure involving feeding of 2-acetylaminofluorene (2-AAF), and in the middle of the 2-AAF treatment, a single necrogenic dose of carbon tetrachloride. Following a recovery period, the rats were fed a diet containing 0.1% nafenopin (NAF), 0.015% perfluorooctanoic acid (PFOA), 0.05% 2,4-dichlorophenoxyacetic acid (2,4-D), 0.05% 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) or 0.05% phenobarbital (PB) as a positive control. When the animals were killed, 7 months after initiation, the incidence of hepatocellular carcinoma was 83, 33 and 16% in the animals treated with NAF, PFOA or 2,4,5-T respectively. No cancers were observed in controls, or in the 2,4,-D groups. In comparison with controls, NAF and PFOA caused a 60-and 24-fold increase inthe peroxisomal beta-oxidation of fatty acids respectively, but only about a 2-fold increase in the catalase activity, 2,4-D and/or 2,4,5-T were much less active in this respect, giving approximately a doubling in the rate of fatty acid oxidation. The specific activity of D-amino acid and glycolate oxidases were significantly depressed, whereas the urate oxidase levels were apparently unaffected by the NAF and PFOA treatment. The results suggest that the selective induction of peroxisomal fatty acid oxidation is consistent with the hypothesis that imbalance between H2O2 overproduction and its destruction could play a role in the modulation of hepatocarcinogenesis by peroxisome proliferators.

2,4,5-Trichlorophenoxyacetic Acid↗

PubMed2005

Genotoxic risk and oxidative DNA damage in HepG2 cells exposed to perfluorooctanoic acid.

Perfluorooctanoic acid (C8HF15O2, PFOA) is widely used in various industrial fields for decades and it is environmentally bioaccumulative. PFOA is known as a potent hepatocarcinogen in rodents. But it is not yet clear whether it is also carcinogenic in humans, and the genotoxic effects of PFOA on human cells have not yet been examined. In this study, the genotoxic potential of PFOA was investigated in human hepatoma HepG2 cells in culture using single cell gel electrophoresis (SCGE) assay and micronucleus (MN) assay. In order to clarify the underlying mechanism(s) we measured the intracellular generation of reactive oxygen species (ROS) using dichlorofluorescein diacetate as a fluorochrome. The level of oxidative DNA damage was evaluated by immunocytochemical analysis of 8-hydroxydeoxyguanosine (8-OHdG) in PFOA-treated HepG2 cells. PFOA at 50-400 microM caused DNA strand breaks and at 100-400 microM MN in HepG2 cells both in a dose-dependent manner. Significantly increased levels of ROS and 8-OHdG were observed in these cells. We conclude that PFOA exerts genotoxic effects on HepG2 cells, probably through oxidative DNA damage induced by intracellular ROS.

Caprylates↗

PubMed1998

An epidemiologic investigation of reproductive hormones in men with occupational exposure to perfluorooctanoic acid.

Perfluorooctanoic acid (PFOA), a potent synthetic surfactant used in industrial applications, is a peroxisome proliferator that has resulted in dose-related increases in hepatic, pancreatic acinar, and Leydig cell adenomas in laboratory animals. In addition, PFOA increased serum estradiol levels through the induction of hepatic aromatase activity. In 1993 and 1995, we conducted two cross-sectional studies of 111 and 80 production workers, respectively, and specifically measured their serum PFOA in relation to several reproductive hormones to determine whether such an effect occurs in humans. PFOA was not significantly associated with estradiol or testosterone in either year's study. A 10% increase in mean estradiol levels was observed among employees who had the highest levels of serum PFOA, although this association was confounded by body mass index. Neither was PFOA consistently associated with the other measured hormones. Our results provide reasonable assurance that, in this production setting, there were no significant hormonal changes associated with PFOA at the serum levels measured. Limitations of this investigation include its cross-sectional design, the few subjects exposed at the highest levels, and the lower levels of serum PFOA measured, compared with those levels reported to cause effects in laboratory animal studies.

Adult↗

PubMed2004

Toxicity of perfluorooctane sulfonic acid and perfluorooctanoic acid to Chironomus tentans.

Two perfluorinated surfactants, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), were evaluated for their toxicity to the aquatic midge, Chironomus tentans. Impetus for this laboratory study originated from a 10-d, in situ field assessment in which C. tentans was exposed to PFOS at concentrations ranging from 300 to 30,000 microg/L. No midges survived these exposures. Midge survival in a preliminary, acute 10-d laboratory test with nominal PFOS concentrations ranging from 0.1 to 100,000 microg/L showed similar toxicity with respect to survival (median lethal concentration [LC50], 45.2 microg/L) and growth (median effective concentration [EC50], 27.4 microg/L). A parallel test using PFOA indicated no significant impacts on survival or growth. A definitive 10-d assay with PFOS concentrations ranging from 1 to 150 microg/L produced an EC50 for growth (87.2+/-11.6 microg/L) of the same order of magnitude as that in the preliminary findings. The same was not true for survival, however, with the LC50 falling outside the range of test concentrations. To further investigate the sensitivity of C. tentans to PFOS, we conducted a chronic life-cycle test using a nominal concentration range of 1 to 100 microg/L. Three of the four endpoints measured-survival, growth, and emergence-were significantly affected, with EC50 values of 92.2+/-3.1, 93.8+/-2.6, and 94.5+/-3.2 microg/L, respectively. Reproduction was not affected by those PFOS concentrations at which females emerged. The results of the present study indicate that PFOS toxicity thresholds for C. tentans are as much as three orders of magnitude lower than those reported for other aquatic organisms but, at present, are approximately two orders of magnitude higher than those concentrations typically observed in aquatic environments.

Alkanesulfonic Acids↗

PubMed1993

Further studies on the involvement of selenium in peroxisome proliferation in rat liver. Comparison of effects with clofibric acid and perfluorooctanoic acid and the pharmacokinetics of [14C]clofibrate.

Most effects of the peroxisome proliferator clofibrate on rat liver are marginal or absent in selenium (Se) deficiency. The purpose of the present study was to determine whether the uptake or distribution of clofibrate is altered by Se deficiency. Rats were fed a Se-adequate or -deficient diet for 10-11 weeks and then these same diets with 0.5% (w/w) clofibric acid (the direct acting hydrolysis product of clofibrate) or 0.02% (w/w) perfluorooctanoic acid (PFOA) for 10 days. Other groups of rats received radiolabeled clofibrate by intubation. Clofibric acid was an ineffective as clofibrate in producing effects (i.e. decreased body weight gain, increases in liver somatic index and protein content of the mitochondrial fraction, and increased activities of catalase and peroxisomal fatty acid beta-oxidation) in the liver of Se-deficient rats. Microsomal omega-hydroxylation was, however, equally induced in both dietary groups. In contrast to clofibric acid, the biological effects of PFOA were not affected by Se status. Furthermore, neither the tissue distribution (plasma, liver and kidney) nor the urinary excretion of 14C was affected by Se deficiency. These results demonstrate that the hydrolysis of clofibrate to clofibric acid is not impaired in the Se-deficient rat. In addition, the involvement of Se in the effects of peroxisome proliferators differs for different members of this structurally heterogeneous group of compounds. It is concluded that the Se-deficient rat may provide valuable information concerning the biochemical mechanism(s) underlying peroxisome proliferation.

Animals↗

PubMed2005

Microcosm evaluation of the fate, toxicity, and risk to aquatic macrophytes from perfluorooctanoic acid (PFOA).

Perfluorooctanoic acid (PFOA) is an anthropogenic contaminant detected in various environmental and biological matrices. This compound is a fluorinated surfactant, belonging to a class of molecules known for persistence and their global distribution, but for which little ecotoxicological data are currently available, especially under field conditions. The environmental fate and toxicity of PFOA to the aquatic macrophytes Myriophyllum sibiricum and M. spicatum were investigated using 12,000 L outdoor microcosms. Replicate microcosms (n = 3) were treated with 0.3, 1, 30, and 100 mg/L PFOA as the sodium salt, plus controls, and assessed at regular intervals over 35 days. PFOA showed no significant dissipation from the water column, except at the greatest concentration, where partitioning from the water column into other compartments is suspected. The two species of Myriophyllum were similar in their sensitivity to PFOA under these simulated field conditions. Toxicity after 14 to 35 days of exposure in the evaluated endpoints for M. spicatum was > or = 5.7 mg/L PFOA for EC10s and > or = 31.8 mg/L PFOA for EC50s and in M. sibiricum was > or = 8.4 mg/L PFOA for EC10s and > or = 35.8 mg/L PFOA for EC50s. The no observed effects concentrations (NOECs) for Myriophyllum spp. were consistently > or = 23.9 mg/L PFOA. A risk assessment for these plant species estimated a negligible probability of toxicity being observed from PFOA exposure at current environmental concentrations.

Caprylates↗

PubMed2005

Gene expression profiles in rat liver treated with perfluorooctanoic acid (PFOA).

Perfluorooctanoic acid (PFOA; Pentadecafluorooctanoic acid) is widely used in various industrial applications. It is persistent in the environment and does not appear to undergo further degradation or transformation. PFOA is found in tissues including blood of wildlife and humans; however, the environmental fate and biological effects of PFOA remain unclear. Microarray techniques of gene expression have become a powerful approach for exploring the biological effects of chemicals. Here, the Affymetrix, Inc. rat genome 230 2.0 GeneChip was used to identify alterations in gene regulation in Sprague-Dawley rats treated with five different concentrations of PFOA. Male rats were exposed by daily gavage to 1, 3, 5, 10, or 15 mg PFOA/kg, body weight (bw)/day for 21 days and at the end of the exposure, liver was isolated and total liver RNA were used for the gene chip analysis. Over 500 genes, whose expression was significantly (p < 0.0025) altered by PFOA at two-fold changes compared to control, were examined. The effects were dose-dependent with exposure to 10 mg PFOA/kg, bw/day, causing alteration in expression of the greatest number of genes (over 800). Approximately 106 genes and 38 genes were consistently up- or down-regulated, respectively, in all treatment groups. The largest categories of induced genes were those involved in transport and metabolism of lipids, particularly fatty acids. Other induced genes were involved in cell communication, adhesion, growth, apoptosis, hormone regulatory pathways, proteolysis and peptidolysis and signal transduction. The genes expression of which was suppressed were related to transport of lipids, inflammation and immunity, and especially cell adhesion. Several other genes involved in apoptosis; regulation of hormones; metabolism; and G-protein coupled receptor protein signaling pathways were significantly suppressed.

Administration, Oral↗

PubMed1998

Mechanisms of peroxisome proliferation by perfluorooctanoic acid and endogenous fatty acids.

1. The effects of endogenous fatty acids and perfluorooctanoic acid (PFOA) and its analogs on peroxisomal acyl CoA oxidase (ACO) and microsomal laurate hydroxylase (LH) activities were evaluated in primary cultures of rat hepatocytes and activation of peroxisome proliferator-activated receptor alpha (PPARalpha) in CV-1 cells. The rank order for the stimulation of ACO activity in hepatocytes for selected compounds was PFOA >> octanoic acid>octanedioic acid, perfluorooctanol (inactive). Increases in ACO activity by PFOA, like those of ciprofibrate, were associated with a marked increase in peroxisome number and cytosolic occupancy volume. Maximal effects of ciprofibrate and PFOA on the stimulation of ACO activity were not additive, suggesting that these two compounds share a common pathway of peroxisome proliferation. 2. Saturated monocarboxylic acids of C4 to C18 chain length were inactive, and, among dicarboxylic acids, only small elevations (40-45%) in ACO activity were observed with the long-chain C12 and C16 dioic acids. Of the C18 fatty acids tested, only oleic and linoleic acids, at 1 mM, produced a two- to three-fold elevation in ACO and LH activities. In comparison with endogenous fatty acids, PFOA was more potent and exhibited a different time course and greater magnitude of stimulation of ACO and LH activities in cultured hepatocytes. 3. Addition of mitochondrial beta-oxidation inhibitors (3-mercaptopropionic and 2-bromooctanoic acids) did not alter ACO activity in the presence of octanoic acid or octanedioic acid; nor did they modify the stimulation of ACO activity by PFOA. The carnitine palmitoyltransferase I inhibitor 2-bromopalmitic acid produced a 2.5-fold increase in ACO stimulatory activity and reduced both ciprofibrate- and PFOA-mediated stimulations of ACO activity. 4. Cycloheximide treatment reduced PFOA- and ciprofibrate-induced ACO activities; however, the response to oleic acid was not blocked and increased slightly. 5. In rat and human PPARalpha transactivation assays, the rank order of activation was ciprofibrate > PFOA > oleic acid > or = octanoic acid > octanedioic acid or perfluorooctanol (inactive). PFOA, ciprofibrate and oleic acid were activators of rPPARalpha at concentrations that correlated favorably with the changes in ACO activity in cell culture. Octanoic acid did not increase ACO activity and was a weak activator of PPARalpha. 6. Our findings suggest that fatty acids such as oleic acid (endogenous fatty acids) and PFOA (a stable fatty acid) act through more than one pathway to increase ACO activity in rat hepatocytes. We conclude that the potent effects of PFOA are primarily mediated by a mechanism that includes the activation of liver PPARalpha.

Acyl-CoA Oxidase↗

PubMed1993

Mortality among employees of a perfluorooctanoic acid production plant.

Perfluorooctanoic acid (PFOA) has been found at low levels (10 to 100 parts per billion) in sera of the general population and at higher levels in occupationally exposed workers. Although PFOA has been reported to be a promoter of rodent hepatocarcinogenesis and to alter reproductive hormones in humans and rodents, there is little information on human health effects associated with PFOA exposure. The present study examined the relationship between PFOA and mortality using a retrospective cohort mortality design. The cohort consisted of 2788 male and 749 female workers employed between 1947 and 1983 at a plant that produced PFOA. The all-causes standardized mortality ratio was .75 (95% confidence interval [CI], .56 to .99) for women and .77 (95% CI, .69 to .86) for men. Among men the cardiovascular standardized mortality rate was .68 (95% CI, .58 to .80) and the all-gastrointestinal diseases was .57 (95% CI, .29 to .99). There was no significantly increased cause-specific standardized mortality ratio for either men or women. Ten years of employment in exposed jobs was associated with a 3.3-fold increase (95% CI, 1.02 to 10.6) in prostate cancer mortality compared to no employment in PFOA production. There were only six prostate cancer deaths overall and four among the exposed workers; thus, the results must be interpreted cautiously. If prostate cancer mortality is related to PFOA, PFOA may increase prostate cancer mortality by altering reproductive hormones in male workers.

Adult↗

PubMed1991

The modulation of rat liver carcinogenesis by perfluorooctanoic acid, a peroxisome proliferator.

Perfluorooctanoic acid (PFOA) is a peroxisome proliferator. The aim of this study was to test for its ability to act as a positive modulator of hepatocarcinogenesis, in the so-called biphasic (initiation by diethylnitrosamine 200 mg/kg ip followed by treatment with the suspected modulators) and triphasic (initiation by the same dose of diethylnitrosamine followed by a selection procedure for 2 weeks consisting of giving 2-acetylaminofluorene and in the middle of this treatment a single dose of CCl4 followed by treatment with the suspected modulators) protocols of liver carcinogenesis. In both protocols treatment with PFOA increased the incidence of malignant hepatocellular carcinoma (HCC). As compared to phenobarbital, the modulating effect of PFOA is more pronounced in a biphasic than in the triphasic protocol. In parallel with positive modulation of HCC, PFOA also selectively induced the peroxisomal acyl-CoA oxidase activity and, to a lesser extent, catalase activity.

Acyl-CoA Oxidase↗

PubMed2005

Method for the determination of perfluorooctanoic acid in air samples using liquid chromatography with mass spectrometry.

Perfluorooctanoic acid is a completely fluorinated carboxylic acid that is usually used in the ammonium salt form as a processing aid in the production of many fluoropolymers and fluoroelastomers. Ammonium perfluorooctanoate readily dissociates in water to give the ammonium and perfluorooctanoate ions. Perfluorooctanoate has been reported to be present in low levels in human serum in the United States and Europe. This study reports on the development and validation of a method for the determination of perfluorooctanoic acid in air samples. This method uses the Occupational Safety and Health Administration (OSHA) Versatile Sampler (OVS) with a nominal 0.3 micro m filter and polystyrene resin sorbent (XAD-2 or XAD-4) followed by determination of the perfluorooctanoate anion by liquid chromatography mass spectrometry. The method was validated in the range of 0.474 to 47.4 microg/m3 for a 480-L sample. Breakthrough studies showed samples could be collected at 1 L/min for 24 hours or at 15 L/min up to 8 hours without breakthrough. Extract storage stability tests showed that sample extracts in methanol remain stable in glass autosampler vials for up to 13 days following initial injection. Perfluorooctanoic acid stability on OVS tubes was unaffected at both refrigerated and ambient temperatures. The overall average retention efficiency was 92.1% with a pooled RSD95 of 5.8% at five concentration levels (0.474 microg/m3 to 47.4 microg/m3).

Air Pollutants, Occupational↗

PubMed1989

Isolation and purification of perfluorodecanoic and perfluorooctanoic acids from rat tissues.

A procedure for the extraction, separation, and isolation of perfluorodecanoic and perfluorooctanoic acids from biological samples is described. The use of conventional lipid extraction procedures leads to substantial loss of the perfluorinated fatty acids added to tissue. The presence of sulfuric acid in aqueous saline during phase partitioning is essential for the recovery of perfluorodecanoic and perfluorooctanoic acids in the organic phase following their extraction from tissue. The perfluorinated fatty acids are co-eluted with simple lipids from silica gel columns using diethyl ether/trifluoroacetic acid (100:1, v/v). Simple lipids are separated by thin layer chromatography. By substituting trifluoroacetic acid for acetic acid in the developing solvents, perfluorodecanoic and perfluorooctanoic acids migrate with other free fatty acids.

Animals↗

PubMed1992

Regulation of perfluorooctanoic acid--induced peroxisomal enzyme activities and hepatocellular growth by adrenal hormones.

A wide variety of compounds, including hypolipidemic drugs, plasticizers and other industrial chemicals, have been found to cause liver enlargement and hepatic peroxisome proliferation by mechanisms that are unclear. Although thyroid and sex hormones have been shown to modulate the hepatic response to these chemicals, the role of adrenal hormones in these phenomena is not clear, and a few studies have produced conflicting data. Therefore this study was undertaken to investigate the role of adrenal hormones in hepatomegaly and peroxisomal enzyme induction caused by peroxisomal proliferators and to further delineate the interrelationship between these parameters. Because adrenalectomy alters hepatic drug metabolism, we have used the nonmetabolizable proliferator perfluorooctanoic acid. Our data show that hepatomegaly caused by perfluorooctanoic acid depends on corticosterone, the major glucocorticoid in rodents. Liver growth caused by perfluorooctanoic acid appears to be predominantly hypertrophic in nature, and DNA synthesis in response to perfluorooctanoic acid predominates in periportal regions of the liver lobule. Data also show that although induction of peroxisomal beta-oxidation by perfluorooctanoic acid is independent of adrenal hormones, induction of catalase is dependent on the presence of these hormones. This study supports the contention that induction of activities of various peroxisomal enzymes is controlled by different regulatory mechanisms.

Adrenal Cortex Hormones↗

PubMed2005

Sonochemical decomposition of perfluorooctane sulfonate and perfluorooctanoic acid.

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are shown to be globally distributed, environmentally persistent, and bioaccumulative. Although the toxicities of these compounds were reported, the cleanup procedure from the environment is not developed because of their inertness. In this report the sonochemical degradations of PFOS and PFOA to the products through the fission of the perfluorocarbon chains were observed and the half-life times of the PFOS and PFOA degradations under an argon atmosphere determined to be 43 and 22 min, respectively. The shortening of perfluorocarbon chain of PFOS and PFOA leads to the lowering of the toxicity in view of the decrease of the persistence, and the technique would contribute to the remediation of the environmental pollution by these compounds.

Alkanesulfonic Acids↗

PubMed2003

Toxicity and toxicokinetics of perfluorooctanoic acid in humans and animals.

Perfluorooctanoic acid (PFOA) is an octanoic acid derivative to which all aliphatic hydrocarbons are substituted by fluorine. PFOA and its salts are commercially used in various industrial processes. The chemical is persistent in the environment and does not undergo biotransformation. It was reported that PFOA is found not only in the serum of occupationally exposed workers but also general populations. Recent studies have suggested that the biological half-life of PFOA in humans is 4.37 years based on study of occupationally exposed workers. It is increasingly suspect that PFOA accumulates and affects human health, although the toxicokinetics of PFOA in humans remain unclear. In experimental animals, PFOA seems low in toxicity. PFOA is well-absorbed following oral and inhalation exposure, and to a lesser extent following dermal exposure. Once absorbed in the body, it distributes predominantly to the liver and plasma, and to a lesser extent the kidney and lungs. PFOA is excreted in both urine and feces. Biological half-life of PFOA is quite different between species and sexes and the difference is due mainly to the difference in renal clearance. In rats, renal clearance of PFOA is regulated by sex hormones, especially testosterone. PFOA is excreted into urine by active tubular secretion, and certain organic anion transporters are though to be responsible for the secretion. Fecal excretion is also important in the elimination of PFOA. There is evidence that PFOA undergoes enterohepatic circulation resulting in reduced amounts of fecal excretion. Elucidation of the mechanisms of transport in biological systems leads to elimination and detoxification of this chemical in the human body.

Animals↗

PubMed2005

Subcellular distribution and protein binding of perfluorooctanoic acid in rat liver and kidney.

Perfluorooctanoic acid (PFOA) is an organic fluorochemical, and its elimination in rats is markedly sex-dependent. Liver and kidney are two primary tissues of distribution of PFOA in rats. In this study, the subcellular distribution of PFOA in male and female rat liver and kidney was examined. The results demonstrated that PFOA content in the liver cytosol of the female rat was significantly higher (49 +/- 6% of total radioactive residues, TRR) than in the male liver (26 +/- 5% TRR), whereas PFOA distribution in the heavier subcellular fractions, especially the nuclei and cell debris fraction, was marginally higher in male rat liver. In rat kidney, more than 70% of PFOA was distributed in the cytosolic fraction, with no significant difference between sexes. The degree of protein binding of PFOA in rat liver and kidney cytosol was analyzed by two different chromatographic methods. The percentage of protein-bound PFOA in the liver cytosol was found to be approximately 55% in both male and female rats. In contrast, significantly more PFOA was bound to cytosolic proteins in the kidney of male rats (42 +/- 6% TRR) than in females (17 +/- 5% TRR). Ligand blotting analysis revealed that multiple proteins from the liver cytosol, nuclei, and mitochondria fractions were capable of specific binding to PFOA.

Animals↗

PubMed2002

[Determination of perfluorooctanoic acid in plasma by gas chromatography].

A method for the quantitative determination of perfluorooctanoic acid in plasma by gas chromatograph-electron capture detector is described. An HP-1 capillary column (30 m x 0.25 mm i.d. x 0.25 micron) was used. Perfluorodecanoic acid as the internal standard was added to plasma sample, which was then lyophilized. The acids were derivatized to their methyl esters and then extracted into hexane. The calibration curve was linear over a range from 20.00 micrograms/L to 4.00 x 10(3) micrograms/L with a correlation coefficient of 0.9946. The average recovery was 99.2% and the RSD was 0.95%. The detection limit was 6.0 micrograms/L. The level of perfluorooctanoic acid in plasma of related occupational workers was measured. The results showed that this method is accurate and reliable.

Air Pollutants, Occupational↗

PubMed1992

The mechanism underlying the hypolipemic effect of perfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOSA) and clofibric acid.

The influence of the peroxisomal proliferators perfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOSA) and clofibric acid on lipid metabolism in rats was studied. Dietary treatment of male Wistar rats with these three compounds resulted in rapid and pronounced reduction in both cholesterol and triacylglycerols in serum. The concentration of liver triacylglycerols was increased by about 300% by PFOSA. Free cholesterol was increased by both perfluoro compounds. Cholesteryl ester was reduced to 50% by PFOSA as well by clofibrate. In hepatocytes from fed rats, all the compounds resulted in reduced cholesterol synthesis from acetate, pyruvate and hydroxymethyl glutarate, but there was no reduction of synthesis from mevalonic acid. The oxidation of palmitate was also increased in all groups. The perfluoro compounds, but not clofibrate, caused some reduction in fatty acid synthesis. The activity of liver HMG-CoA reductase was reduced to 50% or less in all treatment groups and all three compounds led to lower activity of acyl-CoA:cholesterol acyltransferase (ACAT). Changes in other enzymes related to lipid metabolism were inconsistent. The present data suggest that the hypolipemic effect of these compounds may, at least partly, be mediated via a common mechanism; impaired production of lipoprotein particles due to reduced synthesis and esterification of cholesterol together with enhanced oxidation of fatty acids in the liver.

Alkanesulfonates↗