Action of clofibrate and its analogs in rats dissociation of hypolipidemic effects and the induction of peroxisomal β-oxidation

Harrison, Earl H.

doi:10.1016/0005-2760(84)90344-8

Cited by 22 publications

(7 citation statements)

References 20 publications

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“…In addition, we observed that the most active inducers of mdr2 gene expression were ciprofibrate and clofibrate. These findings are in agreement with previous studies that have compared the hepatic effect of fibrates on peroxisome proliferation in rodent liver [21,37]. It is well known that ciprofibrate and clofibrate are the most active peroxisome proliferators, and therefore our observations suggest that the structural requirements for production of hepatic peroxisome proliferation are also required for mdr2 gene induction.…”

Section: Discussionsupporting

confidence: 93%

“…Because fibrate analogues show marked potency differences on the hypolipidaemic effect and peroxisome proliferation in rodent liver [21,37], we further studied the effect of clofibrate analogues on mdr2 gene expression. The relative level of mdr2 mRNA was estimated by densitometric analysis of Northern-blot membranes and expressed as a percentage of the level found in control mice.…”

Section: Figure 2 Effect Of Clofibrate On the Expression Of The Mdr Gmentioning

confidence: 99%

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Fibrates induce mdr2 gene expression and biliary phospholipid secretion in the mouse

Chianale

Vollrath

Wielandt

et al. 1996

Biochemical Journal

144

109

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Disruption of the murine mdr2 gene leads to the complete absence of biliary phospholipids. We tested the hypothesis that the increase in biliary phospholipid output induced by fibrates is mediated via induction of the hepatic mdr2 gene and its encoded product, the P-glycoprotein canalicular flippase. Increased levels of mdr2 mRNA were observed in the liver of mice treated with different fibrates : ciprofibrate, 660p155 % (as compared with control group) ; clofibrate, 611p77 % ; bezafibrate, 410p47 % ; fenofibrate, 310p52 % ; gemfibrozil, 190p25 % (P 0n05 compared with control group). Induction of expression of the mdr gene family was specific to the mdr2 gene. Two-to three-fold increases in P-glycoprotein immunodetection were evident on the canalicular plasma-membrane domain of clofibrate-and ciprofibrate-treated mice. Biliary phospholipid output increased

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Section: Discussionsupporting

confidence: 93%

Section: Figure 2 Effect Of Clofibrate On the Expression Of The Mdr Gmentioning

confidence: 99%

Fibrates induce mdr2 gene expression and biliary phospholipid secretion in the mouse

Chianale

Vollrath

Wielandt

et al. 1996

Biochemical Journal

144

109

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“…[4,7,81). In the present investigation we have compared the effects of a wide range of known peroxisome proliferators on four parameters known to be associated with peroxisomes, i.e.…”

mentioning

confidence: 99%

Examination of the structural requirements for proliferation of peroxisomes and mitochondria in mouse liver by hypolipidemic agents, with special emphasis on structural analogues of 2‐ethylhexanoic acid

Lundgren

Meijer

DePierre

1987

European Journal of Biochemistry

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We have found here that there are clear structural requirements for peroxisome proliferation (monitored as increases in carnitine acetyltransferase activity, cyanide‐insensitive palmitoyl‐CoA oxidation, catalase and increases in the protein designated PPA 80) in mouse liver. From the investigation of ten structural analogues of 2‐ethylhexanoic acid, it could be concluded that the most effective proliferators all have an ethyl group as the substituent on carbon 2 of the main chain, which consists of six carbons. The further observation from this group of compounds that a charged group is required for effective proliferation leads us to speculate that such a group is involved in the molecular mechanism as well. Many, but not all, of the effective peroxisome proliferators in a second group of compounds contain a phenoxy group, often with a substituted α carbon. Interestingly, the 2,4‐dichlorophenoxyacetic and 2,4,5‐trichlorophenoxyacetic acids are both effective peroxisome proliferators, but the closely related p‐chlorophenoxyacetic acid is inactive in this respect, indicating that the chlorine atom at position 2 must be essential to the process in these cases. The results presented here also indicate that the structural requirements for proliferation of mitochondria are similar to those for proliferation of peroxisomes. Certainly, the most effective peroxisome proliferators also cause large increases in ‘mitochondrial’ protein and cytochrome oxidase activity, i.e. there is an obvious qualitative correlation.

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“…Although the structural requirements for peroxisome proliferation are not fully understood, an acidic function or a derivative with an acidic function, appears to be necessary (Harrison, 1984;Lundgren et al, 1987). These studies identified additional chemical structures that are potent peroxisome proliferators, all of which have an acidic function or appear to be readily metabolized to one, emphasizing the importance of the isobutyric acid substituent of the malecule, and diminishing the apparent need for the phenoxy portion.…”

Section: Perspectivesmentioning

confidence: 93%

Chemical Structure-Activity Relationships: Peroxisome Proliferation and Lipid Regulation in Rats

McGuire¹,

Gray²,

Iglesia³

1992

Journal of the American College of Toxicology

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Studies described here address structure-activity relationships of novel hypolipidemic agents that induce peroxisome proliferation. Male rats were given equivalent doses of three well-studied fibrates, fibrate amides, and structurally dissimilar agents. Aryloxyalkanoic acids, amide analogs, and thio, benzimidazole, phenylpiperazine, and oxazole derivatives induced peroxisome proliferation and decreased plasma cholesterol and triglyceride levels. These compounds contain an acidic function or appear to be readily metabolized to a derivative with an acidic function. Substitution of this substituent with an adamantyloxy eliminated peroxisome proliferation and induced contrasting effects on the lipid profile, substantially increasing triglycerides. A direct correlation was established between hepatocellular peroxisome proliferation and plasma high-density lipoprotein (HDL)+holesterol levels. HY PERLIPLDEMIAThere is strong evidence that plasma high-density lipoprotein (HDL) promotes the removal of cholesterol from extrahepatic tissues, such as the arterial wall, resulting in its ultimate transport to the liver for degradation and excretion (Gordon et al., 1986). The main factor in the development of atherosclerotic plaque is excess low-density lipoprotein (LDL)-cholesterol. Therefore, therapeutic agents are being developed to reduce plasma LDLcholesterol, or to elevate HDL-cholesterol, thus effecting beneficial changes in the lipid profile. While recognizing beneficial health effects, hepatomegaly and hepatic peroxisome proliferation in rodents, as well as hepatocellular carcinoma that ensue after long-term administration, cannot be ignored. Studies addressing chemical structure-

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Action of clofibrate and its analogs in rats dissociation of hypolipidemic effects and the induction of peroxisomal β-oxidation

Cited by 22 publications

References 20 publications

Fibrates induce mdr2 gene expression and biliary phospholipid secretion in the mouse

Fibrates induce mdr2 gene expression and biliary phospholipid secretion in the mouse

Examination of the structural requirements for proliferation of peroxisomes and mitochondria in mouse liver by hypolipidemic agents, with special emphasis on structural analogues of 2‐ethylhexanoic acid

Chemical Structure-Activity Relationships: Peroxisome Proliferation and Lipid Regulation in Rats

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