Endogenous ligands of Aryl hydrocarbon receptor may play an important role in DNA damage responses

Abstract

Aryl hydrocarbon receptor (AhR) was initially discovered as a cellular protein involved in mediating the detoxification of xenobiotic compounds including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Subsequent studies have identified several families of metabolic products as endogenous AhR agonists such as 6-Formylindolo[3,2-b] carbazole (FICZ) and kynurenine and revealed important physiological roles of AhR in the regulation of metabolic homeostasis and immune responses. Recently, we found that treatment with DNA damage agents including etoposide, doxorubicin, and hexavalent chromium resulted in elevated levels of AhR and CYP1A2, the latter being an AhR transcriptional target. Moreover, we found that treatment with the oxidant hydrogen peroxide stimulated AhR expression, which was also accompanied by enhanced expression of CYP1A2. It has been shown that hydrogen peroxide is capable of converting tryptophan into FICZ in vitro. Thus, we speculated that oxidant-induced activation of the AhR axis was mediated through the generation of AhR ligand(s) in vivo. Supporting this, we showed that pre-incubation of tryptophan that was dissolved in PBS with hydrogen peroxide elicited a rapid induction of CYP1A2 expression with an kinetics similar to that of FICZ. Given that a common feature of treatment with etoposide, doxorubicin, and hexavalent chromium is the generation of reactive oxygen species in vivo, we propose that enhanced expression of AhR by these DNA damage agents is primarily due to an elevated level of tryptophan metabolic products including FICZ and that the AhR signaling axis may play a significant role in limiting the extent of DNA damage caused by these compounds.