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Functional Characterization of the Promoter of Human Carbonyl Reductase 1 (CBR1). Role of XRE Elements in Mediating the Induction of CBR1 by Ligands of the Aryl Hydrocarbon Receptor

Department of Pharmaceutical Sciences, the State University of New York at Buffalo, Buffalo, New York (S.S.L., X.C., V.G.-C., J.G.B.); Department of Pharmaceutical Sciences, St. Jude Children Research Hospital, Memphis, Tennessee (E.G.S.)

Human carbonyl reductase 1 (CBR1) metabolizes a variety of substrates, including the anticancer doxorubicin and the antipsychotic haloperidol. The transcriptional regulation of CBR1 has been largely unexplored. Therefore, we first investigated the promoter activities of progressive gene-reporter constructs encompassing up to 2.4 kilobases upstream of the translation start site of CBR1. Next, we investigated whether CBR1 mRNA levels were altered in cells incubated with prototypical receptor activators (e.g., dexamethasone and rifampicin). CBR1 mRNA levels were significantly induced (5-fold) by the ligand of the aryl hydrocarbon receptor (AHR) -naphthoflavone. DNA sequence analysis revealed two xenobiotic response elements (_–122XRE and _–5783XRE) with potential regulatory functions. CBR1 promoter constructs lacking the _–122XRE showed diminished (9-fold) promoter activity in AHR-proficient cells incubated with -naphthoflavone. Fusion of _–5783XRE to the _–2485CBR1 reporter construct enhanced its promoter activity after incubations with -naphthoflavone by 5-fold. Furthermore, we tested whether the potent AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced Cbr1 expression in Ahr^+/– and Ahr^–/– mice. TCDD induced hepatic Cbr1 mRNA (TCDD, 2-fold) and Cbr1 protein levels (TCDD, 2-fold) in Ahr^+/– mice compared with vehicle-injected controls. In contrast, no significant Cbr1 mRNA and Cbr1 protein induction was detected in livers from Ahr^–/– mice treated with TCDD. These studies provide the first insights on the functional characteristics of the human CBR1 gene promoter. Our data indicate that the AHR pathway contributes to the transcriptional regulation of CBR1.

Address correspondence to: Dr. Javier G. Blanco, 545 Cooke Hall, Department of Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14260-1200. E-mail: jgblanco{at}buffalo.edu