Peroxisome proliferation in cultured rat hepatocytes produced by clofibrate and phthalate ester metabolites

Gray, Tim J.B.; Beamand, J.A.; Lake, Brian G.; Foster, John R.; Gangolli, S.D.

doi:10.1016/0378-4274(82)90087-x

Cited by 97 publications

(25 citation statements)

References 11 publications

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“…Certainly, in the cell culture studies no compound was truly negative, in that they all produced some stimulation of enzyme activities. We have previously demonstrated increases in peroxisome numbers in rat hepatocyte cultures after treatment with MEHP and other peroxisome proliferators (14,26,27). Although hepatocyte cultures cannot compensate for differences in compound phar- macokinetics as well as possible differences between in vivo and in vitro metabolism; the present studies indicate the potential usefulness of cell cultures as a rapid and economical screen for the induction of peroxisomal enzyme activities.…”

Section: Discussionmentioning

confidence: 58%

Hepatic Effects of Phthalate Esters and Related Compounds. In Vivo and In Vitro Correlations

Lake¹,

Gray²,

Gangolli³

1986

Environmental Health Perspectives

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The hepatic effects of phthalate esters and related compounds on peroxisomal and microsomal enzyme activities were investigated in the intact animal and in primary hepatocyte cultures. In vitro studies with a series of phthalate monoesters demonstrated structure activity differences in the induction of the specific peroxisomal marker KCN-insensitive palmitoyl-CoA oxidation and also of carnitine acetyltransferase. These effects could be reproduced in vivo, and potency differences were also observed between di(2-ethylhexyl) phthalate (DEHP) and its straight-chain isomer, di-n-octyl phthalate. In in vivo studies, DEHP, mono(2-ethylhexyl) phthalate, and clofibrate/clofibric acid produced large increases in liver size and peroxisomal enzyme activities in Sprague-Dawley rats and Chinese hamsters, but had less effect in Syrian hamsters. These effects could be largely reproduced in vitro where good responses were obtained with rat and Chinese hamster hepatocytes, but either little or no effect with Syrian hamster and DunkinHartley guinea pig hepatocytes. Both DEHP and clofibrate appeared to induce similar form(s) of microsomal cytochrome P-450 which exhibited a high specificity towards lauric acid hydroxylation. With a range of hypolipidemic agents, including phthalate monoesters, a good correlation was observed between the induction of peroxisomal and microsomal enzyme activities in rat hepatocyte cultures. These results thus demonstrate a good relationship between the in vivo and in vitro effects of phthalate esters and related compounds and suggest that hepatocyte cultures may be useful for further studies on the hepatic effects of peroxisome proliferators.

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Section: Discussionmentioning

confidence: 58%

Hepatic Effects of Phthalate Esters and Related Compounds. In Vivo and In Vitro Correlations

Lake¹,

Gray²,

Gangolli³

1986

Environmental Health Perspectives

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“…Eventually, the discovery of several other fibrate drugs such as ciprofibrate, bezafibrate, fenofibrate, and gemfibrozil has revolutionized lipid-lowering research. However, the enthusiasm has been short-lived, because prolonged use of some of these drugs like clofibrate and ciprofibrate causes peroxisome proliferation leading to hepatomegaly and tumor formation in the liver of rodents [18][19][20][21][22]. Therefore, there are concerns about widespread use of these drugs in humans.…”

Section: Fibratesmentioning

confidence: 99%

Lipid-lowering drugs

Pahan

2006

Cell. Mol. Life Sci.

198

140

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Although a change in life-style is often the method of first choice for lipid lowering, lipid-lowering drugs, in general, help to control elevated levels of different forms of lipids in patients with hyperlipidemia. While one group of drugs, statins, lowers cholesterol, the other group, fibrates, is known to take care of fatty acids and triglycerides. In addition, other drugs, such as ezetimibe, colesevelam, torcetrapib, avasimibe, implitapide, and niacin are also being considered to manage hyperlipidemia. As lipids are very critical for cardiovascular diseases, these drugs reduce fatal and nonfatal cardiovascular abnormalities in the general population. However, a number of recent studies indicate that apart from their lipid-lowering activities, statins and fibrates exhibit multiple functions to modulate intracellular signaling pathways, inhibit inflammation, suppress the production of reactive oxygen species, and modulate T cell activity. Therefore, nowadays, these drugs are being considered as possible therapeutics for several forms of human disorders including cancer, autoimmunity, inflammation, and neurodegeneration. Here I discuss these applications in the light of newly discovered modes of action of these drugs.

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“…Peroxisomal activation in cultured rat hepatocytes with these peroxisome proliferators have already been demonstrated (Gray et al, 1982;Bieri et al, 1984;Thangada et al, 1989;Dirven et al 1993;Krijt et al, 1993). Primary cultures of rat hepatocytes have been employed to investigate the effects of these chemicals.…”

mentioning

confidence: 99%

Inhibition of peroxisomal degradation by 3-methyladenine (3MA) in primary cultures of rat hepatocytes

Kondo

Makita

1997

Anat. Rec.

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Peroxisome proliferation in cultured rat hepatocytes produced by clofibrate and phthalate ester metabolites

Cited by 97 publications

References 11 publications

Hepatic Effects of Phthalate Esters and Related Compounds. In Vivo and In Vitro Correlations

Hepatic Effects of Phthalate Esters and Related Compounds. In Vivo and In Vitro Correlations

Lipid-lowering drugs

Inhibition of peroxisomal degradation by 3-methyladenine (3MA) in primary cultures of rat hepatocytes

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