Fine Structural Changes in the Hepatic Microbodies of Rats Treated With Hypolipidemic Agents, Gemfibrozil and Clofibrate

Fukuda, Kuniaki; Shindo, Hideyo; Yamashina, Shohei; Mizuhira, Vinci

doi:10.1267/ahc.11.432

Cited by 13 publications

(3 citation statements)

References 29 publications

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“…In other liver cells, these structures were less frequent (10 to 50% peroxisomes contained these tubules). Double-walled tubular structures such as these were not noted in the livers of Sprague-Dawley rats fed gemfibrozil (Kurtz et al, 1976), but were observed in another strain of rat by Fukuda et al (1978). The double-walled tubular structures induced by gemfibrozil, were similar to those described previously in the livers of rats fed clofibrate (Reddy & Svoboda, 1973), dimethrin (Hruban etal.,1974), and RMI-14514 (Yarrington etal.,1981).…”

Section: Morphological Changessupporting

confidence: 75%

“…Similar results were obtained by Kahonen & Ylikahri (1979) with gemfibrozil. The reasons for this discrepancy are not clear, but it is interesting to point out that these two agents induce tubular transformation of the peroxisome matrix (Fukuda et al, 1978;Yarrington et al, 1981). It is conceivable that these tubules represent carnitine acetyltransferase crystals and that these structures do not readily solubilize to yield enzyme activity.…”

Section: Morphological Changesmentioning

confidence: 99%

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Evaluation of Selected Hypolipidemic Agents for the Induction of Peroxisomal Enzymes and Peroxisome Proliferation in the Rat Liver

et al. 1983

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There is a considerable interest in developing potent and safe hypolipidemic drugs for the prevention and management of coronary heart disease in man. In rodents, many of these hypolipidemic compounds induce hepatomegaly, proliferation of peroxisomes and a polypeptide with an approximate mol. wt. of 80000 in liver cells. In the present study, we have examined 10 hypolipidemic compounds for the induction of peroxisome proliferation associated 80000 mol. wt. polypeptide (polypeptide PPA-80), peroxisomal enzymes and peroxisome proliferation in rat liver, in view of the emerging evidence that hepatic peroxisome proliferators as a class are carcinogenic in rats and mice. All ten compounds, fenofibrate (isopropyl-[4-( p-chlorobenzoyl)2-phenoxy-2-methyl] propionate; LS 2265 (taurine derivative of fenofibrate); bezafibrate (2-{4-(2-[4-chlorobenzamido)ethyl] phenoxy}-methyl propionic acid; gemfibrozil (5-2[2,5-dimethylphenoxy]2-2-dimethylpentanoic acid); methyl clofenapate (methyl-2-[4-( p-chlorophenyl)phenoxy]-2-methyl propionate); DG 5685 (5-[4-phenoxybenzyl] trans-2-(3-pyridyl)1,3-dioxane), DH6463 (5-[4-phenoxybenzyl] trans-2-(3-pyrimidinyl)-1,3-dioxane); tiadenol(bis[hydroxyethylthio]-7, 10-decane); ciprofibrate (2,-[4-{2,2-dichlorocyclopropyl}-phenoxy]2-methyl propionic acid) and RMI-14,514 ([5-tetradecycloxyl-2-furancarboxylic acid), produced a marked but variable increase in the activities of peroxisomal enzymes catalase, carnitine acetyltransferase, heat-labile enoyl-CoA hydratase and the fatty acid β-oxidation system and in the amount of polypeptide PPA-80 as demonstrated by SDS-polyacrylamide gel electrophoresis. The peptide map patterns of polypeptide PPA-80 in liver induced by these compounds were strikingly similar. The ultrastructural studies demonstrate that fenofibrate, ciprofibrate, LS 2265, DG 5685 and DH 6463 can induce proliferation of peroxisomes in liver cells of rats, and further confirm the previous reports of hepatic peroxisome proliferative activity of methyl clofenapate, tiadenol, bezafibrate, gemfibrozil and RMI-14514, as shown morphologically. Whether these structurally unrelated chemicals or their metabolite(s) directly activate the peroxisome specific genes to induce this multi-enzyme system or they exert their action on peroxisomes indirectly by causing fatty acid overload in hepatocytes remains to be elucidated. These chemicals offer a simple and reproducible means of stimulating peroxisomal enzymes in liver and should serve as useful tools, for evaluating the implications of hepatic peroxisome proliferation and in elucidating the mechanism of peroxisome proliferator-induced carcinogenesis.

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Section: Morphological Changessupporting

confidence: 75%

Section: Morphological Changesmentioning

confidence: 99%

Evaluation of Selected Hypolipidemic Agents for the Induction of Peroxisomal Enzymes and Peroxisome Proliferation in the Rat Liver

et al. 1983

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“…Peroxisomesconstitute unique, natural subcellular markers in the liver cell (14,39). Their induction has been well studied in male rat liver under the influence of hypolipidemics (1,18,26,38,43,44,51,61,63,77,85), a finding originally reported with clofibrate (37). Some agents modify the internal structure of the organelle (26,85), ( Figure 5).…”

Section: Additional Studies and Observations Pertaining To Hvpolipidementioning

confidence: 82%

Hypolipidemics Carcinogenicity and Extrapolation of Experimental Results for Human Safety Assessments

Iglesia¹,

Farber

1982

Toxicol Pathol

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Dyslipoproteinemias represent a group of disorders closely related to alterations of cholesterol and triglycerides. The alterations of these lipids are considered Important risk factors In coronary heart disease and indicate the need for clinically effective and safe drugs.Hypolipidemic agent therapy, however,does not appear without risk since the administration of these agents is by necessity, on a long-term basis. In the conduct of animal safety studies with some hypolipidemics, hyperplastic nodules or tumors developed in the liver of rodents. Data from the literature seem to indicate that the tumor response in rodents varies with the type of hypolipidemic drug administered. This paper summarizes the studies with the new lipid-regulating agent gemfibrozil. Aside from conventional long-term studies in rodents, the ultrastructural aspects of the liver were analyzed in several species and genotoxicity assays and short-term tests for hepatocarcinogenicity were conducted. Thus, it was possible to obtain an overview of these biological phenomena in order to allow for safety extrapolations. The biological behavior of these liver nodules showed that gemfibrozil and clofibrate-induced hepatocytes had not undergone malignant transformation.

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Quantitative Microscopy Comparison of Peroxisome Proliferation by the Lipid-Regulating Agent Gemfibrozil in Several Species

Gray

Iglesia

1984

Hepatology

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Peroxisome proliferation, a well-documented subcellular reaction which follows the administration of hypolipidemic agents, has been well studied in rodents. However, quantitative studies of this phenomenon in other species of laboratory animals are not readily available even though these species are commonly used as predictors of tolerance or safety in humans. The quantitative stereologic studies reported here compared the effects of the new hypolipidemic agent gemfibrozil on hepatic peroxisomes of monkeys, dogs, hamsters and rats of both sexes under several treatment schedules. Gemfibrozil was administered to rats at 300 mg per kg per day for 1 year in the diet; to hamsters at 400 mg per kg per day for 2 weeks by diet admixture; to dogs at 300 mg per kg per day in gelatin capsules for 1 year; and to monkeys at 300 mg per kg day for 3 months by gavage. These dose levels were selected on the basis of tolerance from preliminary studies in each species. At the end of each experimental interval, liver samples were processed for quantitative microscopy. Peroxisomes from male rats were enlarged and the number of peroxisomes per cell were increased 7-fold over controls, resulting in a 20-fold increased peroxisome volume per cell. Statistically, significant increases also occurred in female rats and the difference between treated and controls was 3-fold for both number and volume of peroxisomes per cytoplasmic unit volume. In hamsters, peroxisomes were proliferated and were of significantly smaller size to the extent that the volume of cytoplasm occupied by peroxisomes was not significantly changed. In dogs, the number of peroxisomes per cell was increased and the volume fraction was significantly increased in females only. The number of peroxisomes in young monkeys did not change after treatment, and the peroxisome volume was decreased in males and increased in females. Aged monkeys had increased number of peroxisomes per hepatocyte with increased volume fraction. These results indicate significant differences in the magnitude and direction of peroxisome changes, reflecting species-dependent organelle response to hypolipidemic agents. The order of susceptibility of peroxisome proliferation in laboratory animals is dog less than monkey less than hamster less than rat.

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Fine Structural Changes in the Hepatic Microbodies of Rats Treated With Hypolipidemic Agents, Gemfibrozil and Clofibrate

Cited by 13 publications

References 29 publications

Evaluation of Selected Hypolipidemic Agents for the Induction of Peroxisomal Enzymes and Peroxisome Proliferation in the Rat Liver

Evaluation of Selected Hypolipidemic Agents for the Induction of Peroxisomal Enzymes and Peroxisome Proliferation in the Rat Liver

Hypolipidemics Carcinogenicity and Extrapolation of Experimental Results for Human Safety Assessments

Quantitative Microscopy Comparison of Peroxisome Proliferation by the Lipid-Regulating Agent Gemfibrozil in Several Species

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