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 (Per-ARNT-Sim) ligand-activated transcription factor (TF). Activation 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 three basic mechanisms. The first mechanism is 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 mechanisms of peroxisome proliferator-activated receptor (PPAR)α/β-, estrogen receptor-, and the AHR-mediated toxicity are described in detail to illustrate the various mechanisms that have been experimentally determined.