Peroxisomal fatty acid oxidation is selectively inhibited by phenothiazines in isolated hepatocytes

Experiments with chlorpromazine, an inhibitor of peroxisomal carnitine octanoyltransferase, have led to the proposal that peroxisomal 0-oxidation which was depressed by the phenothiazine in isolated hepatocytes (1) was dependent on carnitine (2). On the other hand, the inhibition of both cytochrome c oxidase and chlorpromazine palmitoyltransferase activities (2) were proposed as the cause of the reduced ketone body formation from long-

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“…the pel--osisomal htt! acid oxidation is imp:~ir-cd i t ) 1.ir.o as attcstcii I ) ! the deficient o\idation of \.ti-> long-chain ti~tt!…”

Section: Administrution To Mice Oj'u 05% Chlorpromuzine-c'ontuiningmentioning

confidence: 99%

“…chain fatty acids (1) in isolated hepatocytes incubated in the presence of chlorpromazine at concentrations between 0.4 to 1.0 mM.…”

mentioning

confidence: 99%

Peroxisomal Proliferation in Heart and Liver of Mice Receiving Chlorpromazine, Ethyl 2(5(4-Chlorophenyl)Pentyl) Oxiran-2-Carboxylic Acid or High Fat Diet: A Biochemical and Morphometrical Comparative Study

et al. 1987

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“…Though attention has been paid to inhibitors of the mitochondrial system, there was no description of inhibitors of the peroxisomal system until recently. In 1984, Leighton et al [8] demonstrated the selective inhibition of peroxisomal &oxidation by 3 phenothiazine drugs, of which thioridazine proved to be the most effective. These results were obtained with an in vitro system (isolated rat hepatocytes).…”

Section: Introductionmentioning

confidence: 99%

Thioridazine: a selective inhibitor of peroxisomal β‐oxidation in vivo

Branden

Roels

1985

FEBS Letters

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In vivo administration of the phenothiazine drug, thioridazine, inhibits hepatic peroxisomal fl-oxidation in mice. In starving animals, 3-hydroxybutyrate concentration is not decreased by thioridazine treatment. These results provide the first demonstration of thioridazine as a selective inhibitor of peroxisomal /I-oxidation in intact animals. Thioridazine might supply a tool for simulation of pathological conditions in which peroxisomal #&oxidation is impaired. Peroxisome ~-Oxidation CatalaseIn vivo inkibit~on

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“…Phenothiazines can act by shifting the peroxisomal oxidation of fatty acids from situation A to situation B. This change is associated (isolated hepatocytes [3] and short term influence of phenothiazines in rats) or not (short term influence of phenothiazines in mice and long term influence in rats and mice) with a decreased flux of fatty acids through the peroxisomal @-oxidation assayed by Hz02 production. Other comments are given in the text.…”

Section: Discussionmentioning

confidence: 99%

“…An impairment of the former system resulting in the accumulation of VLCFA in body fluids and tissues exists in patients with peroxisomal diseases [2]. Although phenothiazines were demonstrated in rodent liver to inhibit peroxisomal &oxidation [3,4], no animal model for the chronic depression of this route has been studied.…”

Section: Introductionmentioning

confidence: 99%

Short and long term influence of phenothiazines on liver peroxisomal fatty acid oxidation in rodents

Branden¹,

Vamecq

Dacremont³

et al. 1987

FEBS Letters

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Evidence is given that phenothiazines depress hepatic peroxisomal fatty acid oxidation in vivo. After oral administration to rats thioridazine and chlorpromazine inhibit pcroxisomal p-oxidation, evaluated by Hz02 production, during 2 weeks. In mice, this effect could not be demonstrated. However, in both species VLCFA are increased after short and long term drug administration. Electron microscopy reveals the presence of membranous structures in liver cytoplasm or lysosomes. The inhibition by thioridazine of peroxisoma1 B-oxidation does not lead to hepatic peroxisome proliferation. The activities of enzymes related to fatty acid breakdown are not increased and liver peroxisomes are microscopically normal.

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Peroxisomal fatty acid oxidation is selectively inhibited by phenothiazines in isolated hepatocytes

Cited by 42 publications

References 23 publications

Peroxisomal Proliferation in Heart and Liver of Mice Receiving Chlorpromazine, Ethyl 2(5(4-Chlorophenyl)Pentyl) Oxiran-2-Carboxylic Acid or High Fat Diet: A Biochemical and Morphometrical Comparative Study

Peroxisomal Proliferation in Heart and Liver of Mice Receiving Chlorpromazine, Ethyl 2(5(4-Chlorophenyl)Pentyl) Oxiran-2-Carboxylic Acid or High Fat Diet: A Biochemical and Morphometrical Comparative Study

Thioridazine: a selective inhibitor of peroxisomal β‐oxidation in vivo

Short and long term influence of phenothiazines on liver peroxisomal fatty acid oxidation in rodents

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