Timing is everything: consequences of transient and sustained AhR activity

Abstract

The aryl hydrocarbon receptor (AhR) was implicated as a mediator of xenobiotic toxicity over three decades ago. Although a complete picture continues to elude us, investigations by many laboratories during the ensuing period have revealed much about AhR biology in normal physiological processes, as well as the toxicities induced by the dioxins and related polychlorinated aromatic hydrocarbons. The findings are captured in numerous excellent reviews. This commentary attempts to inject a new perspective on some new as well as frequently overlooked observations in the context of established receptor properties. Specifically, we examine the impact of transient versus sustained receptor activation on AhR biology, and explore the potential role for cytochrome P450 expression in regulating AhR activity amongst various tissues. The growing recognition that AhR action functions through multiple mechanisms serves to further highlight the importance of limiting prolonged receptor activation.

Fig. 1

Multiple mechanisms to regulate aryl hydrocarbon receptor (AhR) activity. The diagram depicts the various mechanisms that have evolved to control AhR activity. (Scheme 1) Agonist-dependent dimerization of AhR with the AhR nuclear translocator (ARNT) concomitant with dissociation of the chaperones hsp90, p23 and immunopilin-like protein XAP2/ARA9/AIP; binding of AhR-ARNT complexes to xenobiotic response elements (XREs); and subsequent transcriptional activation. (Scheme 2) Proteolytic degradation of the activated AhR by the 26S proteosome. (Schemes 3 and 4) Repression of AhR activity by the AhR repressor protein (AhRR). (Scheme 5) Metabolic depletion of AhR agonists by cytochrome P4501A1 (CYP1A1) or related enzymes. Exogenous AhR ligands include halogenated aromatic hydrocarbons (HAHs) and polyaromatic hydrocarbons (PAHs).

Fig. 2

Multiple mechanisms involving aryl hydrocarbon receptor (AhR)-mediated cell signaling. The diagram depicts several mechanisms whereby AhR activity modifies cell signaling. Illustrated is the canonical xenobiotic response element (XRE)-bound AhR/ARNT complex with recruited coactivators (CoA; Scheme 1). AhR participation in transcriptional activation at non-XRE sites through indirect DNA-binding (Scheme 2), or direct DNA binding (Scheme 3). Additionally, two non-genomic modes of action involving AhR-mediated susbtrate (S) proteolysis involving cullin 4B (Scheme 4), and activation of epidermal growth factor receptor (EGFR; Scheme 5) are presented.