Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis.

The chronology and history of characterizing the aromatic hydrocarbon [Ah] battery is reviewed. This battery represents the Ah receptor (AHR)-mediated control of at least six, and probably many more, dioxin-inducible genes; two cytochrome P450 genes-P450 1A1 and 1A2 (Cypla1, Cypla2-and four non-P450 genes, have experimentally been documented to be members of this battery. Metabolism of endogenous and exogenous substrates by perhaps every P450 enzyme, but certainly CYP1A1 and CYP1A2 (which are located, in part, in the mitochondrion), have been shown to cause reactive oxygenated metabolite (ROM)-mediated oxidative stress. Oxidative stress activates genes via the electrophile response element (EPRE) DNA motif, whereas dioxin (acutely) activates genes via the AHR-mediated aromatic hydrocarbon response element (AHRE) DNA motif. In contrast to dioxin, AHR ligands that are readily metabolized to ROMs (e.g. benzo[a]pyrene, beta-naphthoflavone) activate genes via both AHREs and the EPRE. The importance of the AHR in cell cycle regulation and apoptosis has just begun to be realized. Current evidence suggests that the CYP1A1 and CYP1A2 enzymes might control the level of the putative endogenous ligand of the AHR, but that CYPA1/1A2 metabolism generates ROM-mediated oxidative stress which can be ameliorated by the four non-P450 EPRE-driven genes in the [Ah] battery. Oxidative stress is a major signal in precipitating apoptosis; however, the precise mechanism, or molecule, which determines the cell's decision between apoptosis and continuation with the cell cycle, remains to be elucidated. The total action of AHR and the [Ah] battery genes therefore represents a pivotal upstream event in the apoptosis cascade, providing an intricate balance between promoting and preventing ROM-mediated oxidative stress. These proposed endogenous functions of the AHR and [Ah] enzymes are, of course, in addition to the frequently described functions of "metabolic potentiation" and "detoxification" of various foreign chemicals.