Regular ArticleDo Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?
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Cited by (216)
Kupffer cells and liver
2022, Recent Advancements in Microbial Diversity: Macrophages and their Role in InflammationApplication of a combined aggregate exposure pathway and adverse outcome pathway (AEP-AOP) approach to inform a cumulative risk assessment: A case study with phthalates
2020, Toxicology in VitroCitation Excerpt :The association of rodent liver toxicity with binding and activation of PPARα has been clearly established in rodents for both DEHP and DBP, as well as a number of other PPARα agonists (Cattley, 2004; Cattley et al., 1998; Klaunig et al., 2003). However, acute and chronic exposures to PPARα agonists are not associated with tumors in humans or non-human primates (Cattley et al., 1998). The weight of evidence indicates that the PPARα MOA for rodent tumors is not relevant to humans (Felter et al., 2018).
Integrated physiology and systems biology of PPARα
2014, Molecular MetabolismCitation Excerpt :Befitting their name, peroxisome proliferators and other synthetic PPARα agonists cause proliferation of peroxisomes and hepatomegaly in rats and mice in a PPARα-dependent manner [49]. In contrast, neither response is observed in humans (Table 2), which together with the observed lack of effect of PPARα agonists on peroxisomal fatty acid oxidation in humans [249], has led to suggestions that the function of PPARα is fundamentally different between mice and humans, and, partly due to the presumed low expression of PPARα in human liver, that the role of PPARα in human liver is relatively insignificant [250]. Subsequent studies have dispelled those notions, showing that a) PPARα expression is similar in mouse and human liver, b) regulation of lipid metabolic pathways and genes, including peroxisomal fatty acid oxidation, is well conserved between mice and humans [159,173].
A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity
2013, Toxicology and Applied PharmacologyCitation Excerpt :As 3D liver cultures have preserved hepatic function for up to 3 months (Figs. 1, 2 and Supplementary Fig. 1A), this allows the performance of not only single, but also repeated drug-treatment studies. To assess the utility of human and rat 3D liver co-cultures to detect the species-specific effects of liver hepatotoxicants, we assessed the toxicity effect after single or repeated drug-treatments with model drugs such as the peroxisome proliferator activated receptor alpha (PPARα)-agonist and rodent-specific hepatocarcinogen fenofibrate (Cattley et al., 1998; Ohta et al., 2009) or the PPARγ-agonist and human-specific hepatotoxicant troglitazone at physiologically relevant concentrations (Loi et al., 1999; Yokoi, 2010). As 3D liver cultures have preserved hepatic function for up to 3 months (Figs. 1, 2 and Supplementary Fig. 1A), this allows the performance of not only single, but also repeated drug-treatment studies.
PPARα-mediated responses in human adult liver stem cells: In vivo/in vitro and cross-species comparisons
2013, Journal of Steroid Biochemistry and Molecular Biology
The views expressed herein are those of the individual authors, and do not necessarily reflect those of ILSI.
P. Baeuerle
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To whom correspondence should be addressed at International Life Sciences Institute, 1126 16th Street, N.W., Washington, DC 20036-4810.