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Cell-specific Regulation of Human CYP1A1 and CYP1B1 Genes¹

Department of Toxicology, University of Tübingen, 72074 Tübingen, Germany [S. K.], and Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655 [W. F. G.]

In this report, we present a characterization of the cell-specific expression of two human cytochrome P450 genes, CYP1A1 and CYP1B1, by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The TCDD-dependent induction of CYP1A1 has been studied extensively and serves as the prototype response for a TCDD-signaling pathway initiated by the reversible binding of TCDD to an intracellular receptor [designated the aryl hydrocarbon (Ah) receptor]. CYP1A1 is induced by TCDD to high levels (45-fold increase) in the human hepatoblastoma line HepG2 as compared with the human renal adenocarcinoma line ACHN. In contrast, CYP1B1 is induced selectively in ACHN cells. Cell-specific induction of CYP1A1 and CYP1B1 mRNA correlates with comparable changes in the corresponding proteins and results, at least in part, from transcriptional activation. Characterization of the mechanism(s) for the differential regulation of CYP1A1 was carried out. Nuclear extracts obtained from either cell line following treatment with TCDD displayed equivalent binding to oligonucleotide probes for two dioxin-responsive elements located 5'-ward of the CYP1A1 promoter. This result obtained with broken cell fractions was confirmed by an intact cell DNA protection assay. Possible involvement of negative regulators is suggested by the presence of a negative regulatory element in the 5' flanking region of the CYP1A1 gene and the observed superinduction of CYP1A1 mRNA by cycloheximide in TCDD-treated HepG2 cells. Electromobility shift analysis using negative regulatory element probes, however, did not detect quantitative differences in the binding of nuclear extract proteins obtained from either HepG2 or ACHN cells treated with TCDD. These findings indicate that the ligand-dependent activation and dioxin-responsive element binding of the Ah receptor required for CYP1A1 induction in HepG2 cells also can occur in ACHN cells. We conclude that the repression of TCDD-dependent CYP1A1 induction in ACHN cells occurs at the level of transactivation in the Ah receptor signal transduction pathway.

¹ This work was supported in part by Grant Kr1480/2-1 from the Deutsche Forschungsgemeinschaft (to S. K.) and grants from the Chemical Manufacturer's Association (to W. F. G.), General Electric Company (to W. F. G.), and USPHS Grant ES07009 (to W. F. G.).

² To whom requests for reprints should be addressed, at Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, 55 Lake Avenue North, Worcester, MA 01655. Phone: (508) 856-2151; Fax: (508) 856-5080; E-mail: william.greenlee@ummed.edu.

Received 9/23/96. Accepted 2/ 8/97.

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