Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor.

Altered systemic levels of 6-formylindolo[3,2-b]carbazole (FICZ), an enigmatic endogenous ligand for the aryl hydrocarbon receptor (AHR), may explain adverse physiological responses evoked by small natural and anthropogenic molecules as well as by oxidative stress and light. We demonstrate here that several different chemical compounds can inhibit the metabolism of FICZ, thereby disrupting the autoregulatory feedback control of cytochrome P4501 systems and other proteins whose expression is regulated by AHR. FICZ is both the most tightly bound endogenous agonist for the AHR and an ideal substrate for cytochrome CYP1A1/1A2 and 1B1, thereby also participating in an autoregulatory loop that keeps its own steady-state concentration low.

The aryl hydrocarbon receptor (AHR), a novel regulator of human melanogenesis.

Skin cancer, chloracne and hyperpigmentation have been associated with the exposure to environmental contaminants such as polychlorinated biphenyls, dioxins or polycyclic aromatic hydrocarbons. These compounds are xenobiotic high-affinity ligands for the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor with important physiological roles in, for example, the control of cell proliferation and inflammation. We show here that exposure of normal human melanocytes to the most potent dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), results in activation of the AHR signaling pathway and an AHR-dependent induction of tyrosinase activity, the key enzyme of the melanogenic pathway.

The aryl hydrocarbon receptor mediates UVB radiation-induced skin tanning.

Melanogenesis is the vital response to protect skin cells against UVB-induced DNA damage. Melanin is produced by melanocytes, which transfer it to surrounding keratinocytes. Recently, we have shown that the aryl hydrocarbon receptor (AhR) is part of the UVB-stress response in epidermal keratinocytes.

The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans.

Dioxins and other polycyclic aromatic compounds formed during the combustion of waste and fossil fuels represent a risk to human health, as well as to the well being of our environment. Compounds of this nature exert carcinogenic and endocrine-disrupting effects in experimental animals by binding to the orphan aryl hydrocarbon receptor (AhR). Understanding the mechanism of action of these pollutants, as well as the physiological role(s) of the AhR, requires identification of the endogenous ligand(s) of this receptor.