Xenobiotic metabolism, disposition, and regulation by receptors: from biochemical phenomenon to predictors of major toxicities

Abstract

To commemorate the 50th anniversary of the Society of Toxicology, this special edition article reviews the history and current scope of xenobiotic metabolism and transport, with special emphasis on the discoveries and impact of selected "xenobiotic receptors." This overall research realm has witnessed dynamic development in the past 50 years, and several of the key milestone events that mark the impressive progress in these areas of toxicological sciences are highlighted. From the initial observations regarding aspects of drug metabolism dating from the mid- to late 1800's, the area of biotransformation research witnessed seminal discoveries in the mid-1900's and onward that are remarkable in retrospect, including the discovery and characterization of the phase I monooxygenases, the cytochrome P450s. Further research uncovered many aspects of the biochemistry of xenobiotic metabolism, expanding to phase II conjugation and phase III xenobiotic transport. This led to hallmark developments involving integration of genomic technologies to elucidate the basis for interindividual differences in response to xenobiotic exposures and discovery of nuclear and soluble receptor families that selectively "sense" the chemical milieu of the mammalian cell and orchestrate compensatory changes in gene expression programming to accommodate complex xenobiotic exposures. This review will briefly summarize these developments and investigate the expanding roles of xenobiotic receptor biology in the underlying basis of toxicological response to chemical agents.

FIG. 1.

Chemical structures of CAR and PXR ligands.

FIG. 2.

Xenobiotic interactions with PPARβ/δ and PPARγ. Xenobiotics that target PPARβ/δ and PPARγ have been shown to modulate gene expression and produce beneficial phenotypes in humans, in particular for regulation of glucose and lipid homeostasis and/or prevention of toxicity/cancer. Anti-inflammatory activities are also known to be associated with xenobiotics that target these receptors by interfering with other transcription factors (Tf) that modulate gene expression that regulate inflammatory responses. However, xenobiotics could also interfere with these functions leading to toxicity because of dysregulation of essential functions by receptor antagonism. Whether xenobiotic-induced enhancement of receptor-dependent functions directly causes, or contributes to, toxicity is also possible.

FIG. 3.

Overall scheme of AHR activation by an agonist, which induces translocation into the nucleus leading to altered gene expression.

FIG. 4.

Chemical structures of diverse AHR ligands. Each structure shown is an AHR agonist, except SGA360, which exhibits selective activity.

FIG. 5.

Schematic comparison of the nuclear and cytoplasmic activities of the AHR mediated by either agonist or SAhRM activation that leads to altered inflammatory signaling.