Unlike most cytochrome P450 (CYP) enzymes, murine hepatic CYP2A5 is induced during pathological conditions that result in liver injury including hepatotoxicity mediated by xenobiotics, hepatitis caused by various microbial agents and liver neoplasia. Since CYP2A5 metabolizes various important xenobiotics including nicotine and pro-carcinogens such as nitrosamines and aflatoxin B(1), altered gene expression could affect tobacco addiction, hepatotoxicity and hepatocarcinogenesis. This article synthesizes the current knowledge concerning hepatic expression of Cyp2a5 including the transcriptional and post-transcriptional regulatory mechanisms, pathophysiological conditions associated with enzyme induction such as oxidative and endoplasmic reticulum stress and altered lipid and energy homeostasis as well as the known exogenous and putative endogenous substrates. Knowledge of the stimuli responsible for the unique overexpression of CYP2A5 during liver injury may provide clues to a functional role for this enzyme and the impact of variable CYP2A5 expression on xenobiotic metabolism and toxicity, disease development and the adaptive response to hepatocellular stress.

Human cytochrome P450 2A6 (CYP2A6) metabolizes various clinically relevant compounds, including nicotine-and tobaccospecific procarcinogens; however, transcriptional regulation of this gene is poorly understood. We investigated the role of the glucocorticoid receptor (GR) in transcriptional regulation of CYP2A6. Dexamethasone (DEX) increased CYP2A6 mRNA and protein levels in human hepatocytes in primary culture. This effect was attenuated by the GR receptor antagonist mifepristone (RU486; 17␤-hydroxy-11␤-[4-dimethylamino phenyl]-17␣-[1-propynyl]estra-4,9-dien-3-one), suggesting that induction of CYP2A6 by DEX was mediated by the GR. In gene reporter assays, DEX caused dose-dependent increases in luciferase activity that was also prevented by RU486 and progressive truncations of the CYP2A6 promoter delineated DEX-responsiveness to a Ϫ95 to ϩ12 region containing an hepatic nuclear factor 4 (HNF4) ␣ response element (HNF4-RE). Mutation of the HNF4-RE abrogated HNF4␣-and DEX-mediated transactivation of CYP2A6. In addition, overexpression of HNF4␣ increased CYP2A6 transcriptional activity by 3-fold. DEX increased HNF4␣ mRNA levels by 4-fold; however, the amount of HNF4␣ nuclear protein was unaltered. Electrophoretic mobility shift, chromatin immunoprecipitation (ChIP), and streptavidin DNA binding assays revealed that DEX increased binding of HNF4␣ to the HNF4-RE and that an interaction of GR and HNF4␣ occurred at this site. Moreover, ChIP assays indicated that histone H4 acetylation of the CYP2A6 proximal promoter chromatin was increased by DEX that may allow for increased binding of HNF4␣ to the HNF4-RE in human hepatocytes. These findings indicate that increased expression of CYP2A6 by DEX is mediated by the GR via a nonconventional transcriptional mechanism involving interaction of HNF4␣ with an HNF4-RE rather than a glucocorticoid response element.

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Down-regulation of glutathione transferase A1 (GSTA1) expression has profound implications in cytoprotection against toxic by-products of lipid peroxidation produced during inflammation. We investigated the role of hepatic nuclear factor 1 (HNF-1) in repression of human GSTA1 expression by interleukin (IL)-1␤ in Caco-2 cells. In luciferase reporter assays, overexpression of HNF-1␣ increased GSTA1 transcriptional activity via an HNF-1 response element (HRE) in the proximal promoter. In addition, constitutive mRNA levels of GSTA1 and HNF-1␣ rose concurrently in Caco-2 cells with increasing stage of confluence. IL-1␤ reduced GSTA1 mRNA levels at all stages of confluence; however, HNF-1␣ mRNA levels were not altered. IL-1␤ repressed GSTA1 transcriptional activity, an effect that was abolished by mutating the HRE. Similar results were observed in HT-29 and HepG2 cells. Overexpression of HNF-1␣ did not counteract IL-1␤-mediated repression of GSTA1 transcription either in reporter assays or at the mRNA level. Involvement of the transdominant repressor C isoform of variant HNF-1 (vHNF-1C) in GSTA1 repression was demonstrated, because vHNF-1C overexpression significantly reduced GSTA1 transcriptional activity. Finally, IL-1␤ caused concentration-related up-regulation of vHNF-1C mRNA levels and increased binding of vHNF-1C protein to the HRE, whereas HNF-1␣-HRE complex formation was reduced. These findings indicate that IL-1␤ represses GSTA1 transcription via a mechanism involving overexpression of vHNF-1C.