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Regulation of the CYP1A1 Gene by 2,3,7,8-Tetrachlorodibenzo-p-dioxin but Not by -Naphthoflavone or 3-Methylcholanthrene Is Altered in Hepatitis C Virus Replicon-Expressing Cells

Department of Medicine (G.R.A., A.H., L.C.Q.), Department of Pediatrics (I.Q.), School of Medicine, and Department of Pharmaceutical Sciences, School of Pharmacy (H.Y.), University of Colorado at Denver and Health Sciences Center, Denver, Colorado

Exposure to hepatitis C virus (HCV) can lead to the development of cirrhosis and hepatocellular carcinoma. To examine the effects of long-term HCV infection on hepatic cytochrome P450 1A1 (CYP1A1) expression and function, we used a human hepatoma cell line expressing the HCV subgenomic replicon (Huh.8) to evaluate CYP1A1 induction by the aryl hydrocarbon receptor (AhR) ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In this study, we demonstrate that the induction of CYP1A1 expression in Huh.8 cells by TCDD but not by -naphthoflavone or 3-methylcholanthrene was significantly diminished. TCDD exposure of Huh.8 cells resulted in greater than 55% suppression of CYP1A1 transcription compared with the parent cell line Huh7, whereas protein levels and enzyme activities were further diminished. Suppression of CYP1A1 mRNA expression in TCDD-treated Huh.8 cells was partially reversed after pretreatment with the antioxidants N-acetylcysteine and nordihydroguaiaretic acid, suggesting a role for oxidative stress. Induced CYP1A1 message, protein, and enzyme activity were partially restored in an Huh7 cell line expressing the HCV replicon containing a deletion in the nonstructural protein NS5A. Furthermore, adenoviral expression of NS5A in Huh7 partially suppressed TCDD-induced CYP1A1 protein and enzyme activity, implicating this protein in the mechanism of suppression. These findings demonstrate that TCDD-mediated AhR signaling is impaired in hepatocytes in which HCV is present and that NS5A alone or in the presence of other nonstructural proteins of the subgenomic replicon is in part responsible.

Received for publication March 6, 2006.

Accepted for publication June 20, 2006.

Address correspondence to: Dr. Linda C. Quattrochi, Department of Medicine, University of Colorado at Denver and Health Sciences Center, 4200 E. 9th Avenue, Denver, CO 80262. E-mail: Linda.Quattrochi{at}UCHSC.edu

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