Coordinate regulation of Phase I and II xenobiotic metabolisms by the Ah receptor and Nrf2

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with important roles in metabolic adaptation, normal physiology and dioxin toxicology. Metabolic adaptation is based on coordinate regulation of a set of xenobiotic-metabolizing enzymes (XMEs), termed AhR battery. Coordination is achieved by AhR/Arnt-binding to XREs (xenobiotic response elements), identified in the 5′ upstream region of AhR target genes. The AhR battery encodes Phase I and II enzymes. Interestingly, these Phase II genes are linked to the Nrf2 gene battery that encodes enzymes that are essential in protection against oxidative/electrophile stress. Nrf2 binds to AREs (antioxidant response elements) in the regulatory region of a large and distinct set of target genes. Functionally characterized response elements such as XREs and AREs in the regulatory region of target genes may provide a genetic basis to understand AhR- and Nrf2-induced genes. Linkage between AhR and Nrf2 batteries is probably achieved by multiple mechanisms, including Nrf2 as a target gene of the AhR, indirect activation of Nrf2 via CYP1A1-generated reactive oxygen species, and direct cross-interaction of AhR/XRE and Nrf2/ARE signaling. Linkage appears to be species- and cell-dependent. However, mechanisms linking XRE- and ARE-controlled Phase II genes need further investigation. Tightened coupling between Phases I and II by AhR- and Nrf2-induced XMEs may greatly attenuate health risks posed by CYP1A1-generated toxic intermediates and reactive oxygen species. Better recognition of coordinate Phase I and II metabolisms may improve risk assessment of reactive toxic intermediates in the extrapolation to low level endo- and xenobiotic exposure.