Sub-chronic dietary toxicity of potassium perfluorooctanesulfonate in rats

Structural and functional features of different types of cytoplasmic fatty acid-binding proteins

Interactions of flurochemicals with rat liver fatty acid-binding protein

Cytoplasmic Fatty-Acid-Binding Proteins - Their Structure and Genes

The plasticizer di(2-ethylhexyl) phthalate (DEHP), to which humans are extensively exposed, was found to be hepatocarcinogenic in rats and mice. DEHP is potentially set free from objects made of synthetic materials (e.g., those used in medicine). Chronically, the greatest amounts are transferred to persons undergoing hemodialysis (up to 3.1 mg/kg b.w. per day) who would thus be considered the individuals most endangered by tumorigenesis. Although toxicokinetics seem to play a certain unclear role in the course of DEHP-related toxicity, toxicodynamic factors appear more decisive. DEHP is a representative of "peroxisome proliferators" (PP), a distinct group of substances that, in rodents, do not only induce peroxisomes but also specific enzymes in other organelles, organ growth, and DNA synthesis. The cluster of the characteristic effects of PP is generally, although perhaps not quite appropriately summarized as "peroxisome proliferation," and is strongest in the liver. The lowest observed effect level (LOEL) and the no observed effect level (NOEL) of peroxisome proliferation in the rat, as determined by the induction of specific enzymes (peroxisomal beta-oxidation, carnitine-acetyl-transferase, cytochrome P-452), DNA synthesis, and hepatomegaly, may be assumed as 50 and 25 mg/kg b.w. per day, respectively. DEHP and other carcinogenic PP are neither genotoxic nor tumor initiators, but they appear to be tumor promoters, also implicating a threshold level for the carcinogenic effect. Although a causal relationship between a particular effect of peroxisome proliferation and hepatocarcinogenesis is as yet unknown, peroxisome proliferation as a whole phenomenon appears to be associated with the potential of tumor induction, as shown by comparison of the relative strength of individual PP and by comparison of species and organ specificities. Likewise, LOEL and NOEL of rodent carcinogenesis, that is, 300 and 50 to 100 mg/kg b.w. per day, respectively, are above but not too far from the corresponding values for the investigated parameters of peroxisome proliferation. Thus, with respect to dose alone, worst-case exposure in hemodialysis patients is at least 16-fold below the LOEL of any characterized PP-specific effect of DEHP and approximately 100-fold below that of DEHP-related tumorigenesis. Also, primates are less responsive to PP than rats with respect to the investigated biochemical and morphological parameters. If this lower primate responsiveness is extrapolated to estimate carcinogenicity in humans, we might thus arrive at an even larger safety margin than when based on exposure alone. Doses of PP hypolipidemics that had clearly induced several indicators of peroxisome proliferation in rats did not cause any clear-cut enhancements in the peroxisomes of patients, even though most of these hypolipidemics were considerably stronger PP than DEHP. Thus, an actual threat to humans by DEHP seems rather unlikely. Accordingly, hepatocarcinogenesis was neither enhanced in workers exposed to DEHP nor in patients treated with hypolipidemics.

Hepatocarcinogenic Potential of Di(2-Ethylhexyl)phthalate in Rodents and its Implications on Human Risk

Effects of peroxisome proliferators on fatty acid-binding protein in rat liver.

Effects of peroxisome profilators on fatty acid-binding protein in rat liver

Binding properties of liver cytosolic protein for oleic acid, palmitoyl-CoA and bromosulphophthalein (BSP) were compared for rat, mouse and guinea pig. Hepatic cytosol of rat, mouse and guinea pig contained proteins with a molecular weight of ca. 12,000 and had an affinity for [1-14C]-oleic acid. The concentration of fatty acid-binding protein (FABP) was almost the same in livers of the animals of the 3 species and was ca. 50 μg/mg cytosolic protein. Electrophoretic studies revealed that FABP from hepatic cytosol of rat, mouse and guinea pig, purified with affinity chromatography, are distinct from one another in terms of their charge. FABP of rat liver was capable of binding any 3 ligands-oleic acid, palmitoyl-CoA and BSP—at relatively high binding capacity. FABP of mouse liver also bound oleic acid and palmitoyl-CoA to a great extent, but its binding capacity for BSP was only one-third that of rat liver. FABP of guinea pig liver bound less oleic acid and palmitoyl-CoA than rat liver, whereas it had almost the same binding capacity for BSP as rat liver.

Yuka Tachibana

Papers

Effects of peroxisome proliferators on fatty acid-binding protein in rat liver.

Effects of peroxisome profilators on fatty acid-binding protein in rat liver

Species difference of liver cytosolic fatty acid-binding protein in rat, mouse and guinea pig

Effect of clofibric acid and tiadenol on peroxisomal β-oxidation and fatty acid binding protein in intestinal mucosa of rats