Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?

doi:10.1006/rtph.1997.1163

Regulatory Toxicology and Pharmacology

Volume 27, Issue 1, February 1998, Pages 47-60

https://doi.org/10.1006/rtph.1997.1163 Get rights and content

Abstract

The purpose of the workshop “Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?” was to provide a review of the current state of the science on the relationship between peroxisome proliferation and hepatocarcinogenesis. There has been much debate regarding the mechanism by which peroxisome proliferators may induce liver tumors in rats and mice and whether these events occur in humans. A primary goal of the workshop was to determine where consensus might be reached regarding the interpretation of these data relative to the assessment of potential human risks. A core set of biochemical and cellular events has been identified in the rodent strains that are susceptible to the hepatocarcinogenic effects of peroxisome proliferators, including peroxisome proliferation, increases in fatty acyl-CoA oxidase levels, microsomal fatty acid oxidation, excess production of hydrogen peroxide, increases in rates of cell proliferation, and expression and activation of the α subtype of the peroxisome proliferator-activated receptor (PPAR-α). Such effects have not been identified clinically in liver biopsies from humans exposed to peroxisome proliferators or inin vitrostudies with human hepatocytes, although PPAR-α is expressed at a very low level in human liver. Consensus was reached regarding the significant intermediary roles of cell proliferation and PPAR-α receptor expression and activation in tumor formation. Information considered necessary for characterizing a compound as a peroxisome proliferating hepatocarcinogen include hepatomegaly, enhanced cell proliferation, and an increase in hepatic acyl-CoA oxidase and/or palmitoyl-CoA oxidation levels. Given the lack of genotoxic potential of most peroxisome proliferating agents, and since humans appear likely to be refractive or insensitive to the tumorigenic response, risk assessments based on tumor data may not be appropriate. However, nontumor data on intermediate endpoints would provide appropriate toxicological endpoints to determine a point of departure such as the LED₁₀or NOAEL which would be the basis for a margin-of-exposure (MOE) risk assessment approach. Pertinent factors to be considered in the MOE evaluation would include the slope of the dose–response curve at the point of departure, the background exposure levels, and variability in the human response.

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: The views expressed herein are those of the individual authors, and do not necessarily reflect those of ILSI.

: P. Baeuerle

^†: To whom correspondence should be addressed at International Life Sciences Institute, 1126 16th Street, N.W., Washington, DC 20036-4810.

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Regular ArticleDo Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?

Abstract

Biochem. Biophys. Res. Commun.

Food Chem. Toxicol.

Toxicol. Appl. Pharmacol.

Atherosclerosis

Food Chem. Toxicol.

Atherosclerosis

Cell

Atherosclerosis

J. Biol. Chem.

Cell

Toxicology

Toxicol. Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Toxicol. Lett.

J. Biol. Chem.

Fundam. Appl. Toxicol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

J. Biol. Chem.

Regul. Toxicol. Pharmacol.

Cancer Lett.

Toxicol. Appl. Pharmacol.

J. Biol. Chem.

Fundam. Appl. Toxicol.

Mechanistically-based human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis

Hum. Exp. Toxicol.

Comparison of the acute and chronic mitogenic effects of the peroxisome proliferator methylclofenapate and clofibric acid in rat liver

Carcinogenesis

Differential expression of peroxisome proliferator-activated receptors (PPARS)—Tissue distribution of PPAR-α, -β, and -γ in the adult rat

Endocrinology

Toxicokinetics of gemfibrozil in rats, mice and hamsters

Int. Toxicologist

Controlled death (apoptosis) of normal and putative preneoplastic cells in rat liver following withdrawal of tumor promoters

Carcinogenesis

Elevated 8-hydroxydeoxyguanosine in hepatic DNA of rats following exposure to peroxisome proliferator-relationship to carcinogenesis and nuclear localization

Carcinogenesis

Differences in the promoting activities of the peroxisome proliferator Wy-14,643 and phenobarbital in rat liver

Cancer Res.

Age-related susceptibility to the carcinogenic effect of the peroxisome proliferation Wy-14,643 in rat liver

Carcinogenesis

Transformation of mammalian cells by overexpressing H22

Proc. Natl. Acad. Sci. USA

Toxicokinetics (TK) of di-n

Int. Toxicologist

Relationship of oxidative damage to the hepatocarcinogenicity of the peroxisome proliferators di (2-ethylhexyl)phthalate and Wy-14,643

Carcinogenesis

Rat 17β-hydroxysteroid dehydrogenase type IV is a novel peroxisome proliferator-inducible gene

Mol. Pharmacol.

PPAR: A key factor in nutrient/gene interactions

Inducible Transcription

The PPARα–leukotriene B4 pathway to inflammation control

Nature

Control of the peroxisome beta oxidation pathway by a novel family of nuclear hormone receptors

Cell

Differential enzyme inducing activity of peroxisome proliferators in the male syrian hamster

Int. Toxicologist

Hepatocellular DNA synthesis in rats given peroxisome proliferating agents—comparison of Wy-14,643 to clofibric acid, nafenopin and LY171883

Carcinogenesis

Species differences in peroxisome proliferation

Toxicologist

Peroxisome Proliferators: Species differences in response of primary hepatocyte cultures

Ann. N.Y. Acad. Sci.

Liver protein changes in B6C3F1 mice and Syrian hamsters treated with the peroxisome proliferator Wy-14,643

Int. Toxicologist

Peroxisome proliferators and lipid peroxidation in rat liver

Cancer Res.

Regular Article
Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?

Transformation of mammalian cells by overexpressing H₂₂