Showing papers by "Jeffrey M. Peters published in 2018"

The PPARα-dependent rodent liver tumor response is not relevant to humans: addressing misconceptions

Abstract: A number of industrial chemicals and therapeutic agents cause liver tumors in rats and mice by activating the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). The molecular and cellular events by which PPARα activators induce rodent hepatocarcinogenesis have been extensively studied elucidating a number of consistent mechanistic changes linked to the increased incidence of liver neoplasms. The weight of evidence relevant to the hypothesized mode of action (MOA) for PPARα activator-induced rodent hepatocarcinogenesis is summarized here. Chemical-specific and mechanistic data support concordance of temporal and dose–response relationships for the key events associated with many PPARα activators. The key events (KE) identified in the MOA are PPARα activation (KE1), alteration in cell growth pathways (KE2), perturbation of hepatocyte growth and survival (KE3), and selective clonal expansion of preneoplastic foci cells (KE4), which leads to the apical event—increases in hepatocellular adenomas and carcinomas (KE5). In addition, a number of concurrent molecular and cellular events have been classified as modulating factors, because they potentially alter the ability of PPARα activators to increase rodent liver cancer while not being key events themselves. These modulating factors include increases in oxidative stress and activation of NF-kB. PPARα activators are unlikely to induce liver tumors in humans due to biological differences in the response of KEs downstream of PPARα activation. This conclusion is based on minimal or no effects observed on cell growth pathways and hepatocellular proliferation in human primary hepatocytes and absence of alteration in growth pathways, hepatocyte proliferation, and tumors in the livers of species (hamsters, guinea pigs and cynomolgus monkeys) that are more appropriate human surrogates than mice and rats at overlapping dose levels. Despite this overwhelming body of evidence and almost universal acceptance of the PPARα MOA and lack of human relevance, several reviews have selectively focused on specific studies that, as discussed, contradict the consensus opinion and suggest uncertainty. In the present review, we systematically address these most germane suggested weaknesses of the PPARα MOA.

Mechanisms: Xenobiotic Receptor-Mediated Toxicity

Abstract: A common theme in chemically induced mammalian toxicity is the ability of certain chemicals to mediate their effects through activation of members of the nuclear receptor superfamily or the aryl hydrocarbon receptor (AHR), a basic helix–loop–helix/PAS ligand-activated transcription factor. This in turn leads to a myriad of changes in gene expression as these receptors bind to their cognate response elements. Receptor-induced toxicity can be divided into four basic mechanisms, the first being the disruption of the activation pathways involved in normal development and physiological processes. The second mechanism of receptor-mediated toxicity is the ability of the xenobiotic-induced receptor to induce a spectrum of transcriptional activity not normally observed. The third general mechanism of toxicity involves the ability of an activated receptor to increase levels of enzymes that metabolize the receptor ligand to toxic metabolites. The fourth more recently studied mechanism of toxicity involves the interaction of the gut microbiota with host receptors to either modify or directly mediate the toxicity response. The mechanisms of PPARα/β-, estrogen receptor-, and the AHR-mediated toxicity are described in detail to illustrate the various mechanisms that have been experimentally determined.