Mechanisms: Xenobiotic Receptor-Mediated Toxicity

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.