Species Difference in Hepatic Peroxisome Proliferation
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Two hypolipidemic compounds [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid, and 2-chloro-5-(3,5-dimethylpiperidinosulfonyl)benzoic acid (tibric acid) greatly increased the number of peroxisomes (microbodies) in liver cells of rats and mice. This augmented peroxisome population was accompanied by significant elevation of liver catalase activity. These two hypolipidemic peroxisome proliferators are structurally different from ethyl α- p -chlorophenozyisobutyrate (clofibrate) and other hypolipidemic, aryloxyisobutyrate derivatives which cause hepatic peroxisome proliferation. Induction of peroxisome proliferation by these structurally unrelated hypolipidemic compounds suggests a possible relation between hepatic peroxisome proliferation and hypolipidemia.
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Dietary treatment of male C57B1/6 mice with clolibrate, nafenopin or WY‐14.643 resulted in a modest (at most 2‐fold) increase in the total catalase activity in the whole homogenate and mitochondrial fraction prepared from the livers of these animals. On the other hand, the catalase activity recovered in the cytosolic fraction was increased 12‐ to 18‐fold, i.e. 30–35% of the total catalase activity in the hepatic homogenate was present in the high‐speed supernatant fraction after treatment with these peroxisome proliferators. A study of the time course of the changes in peroxisomal and cytosolic catalase activities demonstrated that the peroxisomal activity both increased upon initiation of exposure and decreased after termination of treatment several days after the increase and decrease, respectively, in the corresponding cytosolic activity. This finding suggests that the cytosolic catalase may be on its way to incorporation into peroxisomes.
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Peroxisome proliferation, a phenomenon studied intensively for the past quarter century is a seemingly uniform reaction of the liver to hypolipidemic drugs and some industrial chemicals. However, application of quantitative microscopic techniques revealed unsuspected characteristics, and facilitated the analysis of peroxisome biogenesis, a dynamic process occurring without disruption of the hepatocyte architecture. The rate of peroxisome biogenesis accelerates to a significant degree within a brief period after compound administration, and the peroxisome population can accumulate up to seven times the normal level. Degradation of peroxisomes follows a triphasic curve and the overall rate of elimination is about the same as the rate of accumulation. Quantitative morphometric studies show interspecies differences in peroxisome induction, with rats being the most susceptible species. Hamsters show peroxisome induction although not to the same substantive extent seen in rats. Monkeys and dogs show poor response, but longer-term data are needed.
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Morphometric analysis was performed on liver sections of rats at light (LM) and electron microscopical (EM) level to demonstrate proliferation of peroxisomes after administration of di (2-ethylhexyl)phthalate at dietary levels of 0, 60, 200, 600, 2000 and 6000 mg/kg diet for 2 weeks. Enzyme histochemical demonstration of catalase was carried out to demonstrate the presence of peroxisomes. The results of the LM-morphometric analysis will be compared with those of the biochemical analysis, reported elsewhere. The LM-morphometric data will be tested by EM-morphometry in a limited number of groups. With the LM- as well as the EM-method the volume density of peroxisomes and the number of peroxisomes were significantly increased after administration of 200 mg DEHP/kg diet during 2 weeks. However, LM-morphometry of peroxisomes by enzyme histochemical demonstration of catalase is suitable to compare the capacity of various phthalate esters to induce proliferation of peroxisomes, realising that the measured values of volume density at LM-level are not true values, but relative values. With the catalase reaction, enzyme histochemical morphometry of peroxisomes showed a dose-without-effect of 60 mg DEHP/kg diet.
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The peroxisome is a subcellular organelle that is widely distributed in nature and which carries out both catabolic and anabolic functions (Ann. NY Acad. Sch 386:1-550, 1982). The catabolic functions include respiration (based on the formation and decomposition of H 2 O 2 ) and the ß-oxidation of fatty acids. A number of drugs share the attributes of beingi) hypo-lipidemic, (2) inducers of the peroxisomal ß-oxidation enzyme system, (Lazarow, Science 197: 580-581, 1977), 3) peroxisome proliferators, and 4) carcinogens in rodents. Reddy et al. (Nature 283: 397-398, 1980) have hypothesized that peroxisome proliferators as a class may be carcinogenic Data is presented showing that bezafibrate, at a suitable hypolipidemic dose in rats, induces peroxisomal ß-oxidation but does not cause the striking organelle proliferation commonly observed with hypolipidemic drugs. Similar results have been obtained with clofibrate treatment of female rats. Christiansen et al. (Eur.). Cell Biol. 26: 77-20, 7987) have shown that feeding rats a diet rich in partially hydrogenated marine oils produces changes in the peroxisomes similar to those caused by bezafibrate. Aspirin, which is weakly hypolipidemic and a weak peroxisome proliferator, is apparently not carcinogenic in humans. The evidence indicates that the hypolipidemic effects and the peroxisome proliferative effects of these drugs are largely (although incompletely) dissociable. It suggests the need for considerable caution in evaluating the relationship, if any, between hypolipidemic and carcinogenic effects.
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HLA-B-associated transcript 3 (BAT3) was originally identified as one of the genes located within human major histocompatibility complex. It encodes a large proline-rich protein with unknown function. In this study, we found that a fragment of the BAT3 gene product interacts with a candidate tumor suppressor, DAN, in the yeast-based two-hybrid system. We cloned the full-length rat BAT3 cDNA from a fibroblast 3Y1 cDNA library. Our sequence analysis has demonstrated that rat BAT3 cDNA is 3617 nucleotides in length and encodes a full-length BAT3 (1098 amino acids) with an estimated molecular mass of 114,801 daltons, which displays an 87.4% identity with human BAT3. The deletion experiment revealed that the N-terminal region (amino acid residues 1-80) of DAN was required for the interaction with BAT3. Green fluorescent protein-tagged BAT3 was largely localized in the cytoplasm of COS cells. Northern hybridization showed that BAT3 mRNA was expressed in all the adult rat tissues examined but predominantly in testis. In addition, the level of BAT3 mRNA expression was more downregulated in some of the transformed cells, including v-mos- and v-Ha-ras-transformed 3Y1 cells, than in the parental cells.
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Peroxisomes, also known as microbodies, are the most recently discovered cellular organelles. They are small, with a one-layer membrane, and are associated with several enzymes. Peroxisome proliferators are compounds which induce and increase the quantity of cellular peroxisomes and their enzymes. There are many variations of these compounds, including therapeutic agents, industrial solvents, herbicides, substances added to food to improve taste, and long fatty acids. Experimental exposure to peroxisome proliferators is associated with hepatocellular carcinoma, and peroxisome proliferators are today regarded as complete non-genotoxic carcinogens. In addition, gastric tumours originating from enterochromaffin-like cells have been detected after administrating peroxisome proliferators. Peroxisome proliferators constitute a large group of compounds that may lead to hormone release and tumour development. Peroxisomes and their proliferators are therefore of great importance in the study of hormonal carcinogenesis. This article summarizes peroxisome function and the role of peroxisomes in carcinogenesis and hormone release.
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Peroxisomal disorder
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Cytochemistry
Adrenoleukodystrophy
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