ABSTRACT:We have previously shown that cadmium, a metal that alters cellular redox status, induces CYP2A5 expression in nuclear factor (erythroid-derived 2)-like 2 wild-type (Nrf2 ϩ/ϩ ) mice but not in the knockout (Nrf2 ؊/؊ ) mice. In the present studies, the potential role The mouse CYP2A5 and its human ortholog CYP2A6 mediate the phase I metabolism of a diverse range of toxic compounds, including nitrosamines and aflatoxins (Su and Ding, 2004). These enzymes are predominantly expressed in hepatocytes but are also present in extrahepatic tissue, particularly in the nasal mucosa (Su and Ding, 2004). CYP2A5 enzyme is the major catalyst of coumarin 7-hydroxylation in mouse liver (Lang et al., 1989). Its regulation is complex and unique among other major cytochromes P450 (P450s). It can be induced by structurally unrelated compounds and also by several chemicals and pathophysiological conditions that usually repress other P450 isoforms. The Cyp2a5 gene is induced by classical inducers, such as phenobarbital (Wood and Conney, 1974), and by various hepatotoxic agents, including pyrazole, carbon tetrachloride, and metals (Seubert et al., 2002;Abu-Bakar et al., 2004;Su and Ding, 2004). Elevated CYP2A5 protein was also observed in spontaneous, transplanted, or chemically induced mouse hepatomas (Su and Ding, 2004).Depending on the inducer, the activation of hepatic CYP2A5 can be achieved both by transcriptional and post-transcriptional mechanisms. Transcriptional induction of Cyp2a5 by 2,3,7,8-tetrachlorodibenzo-pdioxin is mediated by the binding of a ligand-activated aryl hydrocarbon receptor (AHR)/aryl hydrocarbon receptor nuclear translocator (ARNT) complex to the xenobiotic response element (XRE) site at the Cyp2a5 distal promoter (Arpiainen et al., 2005). Pyrazole, a hepatotoxin, induces CYP2A5 by a post-transcriptional mechanism involving binding of heterogenous nuclear ribonucleoprotein A1 to the 3Ј-untranslated region of CYP2A5 mRNA, with subsequent stabilization of the mRNA (Glisovic et al., 2003).However, given the structural diversity of the inducers, it is possible that induction of CYP2A5 is not directly related to the nature of the inducing agents, but instead may be an indirect consequence of a