An Overview of Peroxisome Proliferator-Induced Hepatocarcinogenesis

Rao, M. S.; Reddy, Janardan K.

doi:10.2307/3431190

Cited by 17 publications

(22 citation statements)

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“…There have been a number of explanations for the observed hepatocarcinogenicity in rodents. One suggestion was that PPs caused an increase in hydrogen peroxide by altering the activity of the peroxisomal hydrogen peroxide-producing enzymes leading to oxidative stress and DNA damage (Reddy & Rao 1986, Rao & Reddy 1991, Clayson et al 1994. Subsequent data have suggested that PPs can perturb the mechanisms controlling hepatocyte growth and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences

Holden

Tugwood²

1999

Journal of Molecular Endocrinology

187

116

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Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences

Holden

Tugwood²

1999

Journal of Molecular Endocrinology

187

116

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“…Many xenobiotics, including amphipathic carboxylates used as hypolipidemic agents, induce peroxisome proliferation and ultimately hepatocarcinogenesis in rodents (2). These peroxisome proliferators are nongenotoxic carcinogens that apparently act as tumor promoters by modulating the expression of cellular genes involved in growth and differentiation (3,4).…”

mentioning

confidence: 99%

Diverse peroxisome proliferator-activated receptors bind to the peroxisome proliferator-responsive elements of the rat hydratase/dehydrogenase and fatty acyl-CoA oxidase genes but differentially induce expression.

Marcus

Miyata

Zhang

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

156

115

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The ability of peroxisome proliferator-activated receptors (PPARs) to induce expression of a reporter gene linked to a peroxisome proliferator-responsive element (PPRE) from either the rat enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase gene or acyl-CoA oxidase [acyl-CoA:oxygen 2-oxidoreductase, EC 1.3.3.6] gene was examined by transient transfection assays in COS cells. Mouse and rat PPARs, as well as Xenopus PPAR alpha (xPPAR alpha) could induce expression of a reporter gene linked to the hydratase/dehydrogenase PPRE in the presence of the peroxisome proliferators ciprofibrate or Wy-14,643, whereas xPPAR beta and xPPAR gamma were ineffective. A similar induction of expression of a reporter gene linked to the acyl-CoA oxidase PPRE was observed with all PPARs except xPPAR beta. Extracts from cells transfected with PPAR-encoding genes contained factors that bound to both PPREs. In vitro synthesized PPARs could interact weakly with both PPREs; however, binding of each PPAR to both PPREs was significantly increased by the addition of COS cell nuclear extracts, demonstrating that efficient PPAR/DNA binding requires auxiliary cofactors. One cofactor was identified as the 9-cis-retinoic acid receptor, RXR alpha (retinoid X receptor alpha). Cooperative DNA binding and heteromerization between RXR alpha and each of the PPARs could be seen with both PPREs. Our results demonstrate that PPAR/PPRE binding and cooperativity with RXR alpha (and other cofactors) are obligatory but not necessarily sufficient for peroxisome proliferator-dependent transcription induction and that distinct PPREs can selectively mediate induction by particular PPARs.

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“…Several hypotheses have been proposed to account for the formation of liver tumors by peroxisome proliferators in rats and mice (2,(6)(7)(8)(9)(13)(14). If these hypotheses are combined, a role for increased cell replication in peroxisome proliferator-induced hepatocarcinogenicity may be identified.…”

Section: Discussionmentioning

confidence: 99%

“…Because peroxisome proliferators appear to be nongenotoxic carcinogens, it has been suggested that liver tumor formation arises from a sustained "oxidative stress" to the hepatocytes due to an imbalance in the production and degradation of peroxisomal hydrogen peroxide (2,(6)(7)(8)(9). This imbalance is due to the fact that peroxisome proliferators markedly stimulate enzymes of the peroxisomal fatty acid f-oxidation cycle (which generate hydrogen peroxide), whereas only a small increase is observed in catalase activity, and selenium-dependent glutathione peroxidase activity is normally inhibited by these chemicals (7,8,11,12).…”

Section: Introductionmentioning

confidence: 99%

Comparison of the Hepatic Effects of Nafenopin and WY-14, 643 on Peroxisome Proliferation and Cell Replication in the Rat and Syrian Hamster

Lake¹,

Evans²,

Cunninghame³

et al. 1993

Environmental Health Perspectives

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Male Sprague-Dawley rats were fed control diet or diet containing 0.05% nafenopin (NAF) or 0.025% WY-14,643 (WY) and male Syrian hamsters were fed control diet or diet containing 0.25% NAF or 0.025% WY for periods of 1, 15, 40, and 60 weeks. Both NAF and WY produced a sustained increase in liver weight and induction of peroxisomal fatty acid n-oxidation in the rat and Syrian hamster. Replicative DNA synthesis was studied by implanting osmotic pumps containing 13HI thymidine during weeks 0-1, 14-15, 39-40, and 59-60. Cell replication, determined either as the hepatocyte labelling index or by incorporation of radioactivity into liver whole homogenate DNA, was increased in rats given NAF and WY for 1 week. However, only WY produced a sustained increased in cell replication after 15-60 weeks. After 40 weeks, liver nodules and tumors were present in WY-treated rats, and these lesions were observed in all WY-treated and some NAF-treated rats after 60 weeks. In contrast to the rat, no marked effect on replicative DNA synthesis and no liver nodules and tumors were observed in Syrian hamsters given NAF and WY for up to 60 weeks. The rat study demonstrates that liver tumors are produced more rapidly by doses of peroxisome proliferators that produce a sustained stimulation of cell replication, whereas the hamster study suggests that species differences may exist in both peroxisome proliferator-induced cell replication and liver tumor formation.

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An Overview of Peroxisome Proliferator-Induced Hepatocarcinogenesis

Cited by 17 publications

References 0 publications

Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences

Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences

Diverse peroxisome proliferator-activated receptors bind to the peroxisome proliferator-responsive elements of the rat hydratase/dehydrogenase and fatty acyl-CoA oxidase genes but differentially induce expression.

Comparison of the Hepatic Effects of Nafenopin and WY-14, 643 on Peroxisome Proliferation and Cell Replication in the Rat and Syrian Hamster

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