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  • Title: Abundance of aryl hydrocarbon receptor potentiates benzo[a]pyrene-induced apoptosis in Hepa1c1c7 cells via CYP1A1 activation.
    Author: Chung JY, Kim JY, Kim WR, Lee SG, Kim YJ, Park JE, Hong YP, Chun YJ, Park YC, Oh S, Yoo KS, Yoo YH, Kim JM.
    Journal: Toxicology; 2007 Jun 03; 235(1-2):62-72. PubMed ID: 17433523.
    Abstract:
    Although B[a]P-induced apoptosis has been demonstrated in Hepa1c1c7 cells, the cellular signaling pathway(s) by which benzo[a]pyrene (B[a]P) elicits a cytotoxicity-mediated apoptogenic role remains to be elucidated. In this study, we showed that B[a]P induces apoptosis in a p53-mediated and caspase-3-dependent manner, which relates to the accumulation of the S phase of the cell cycle. Importantly, we have shown for the first time that Hepa1c1c7 cells retain a considerably high content of aryl hydrocarbon receptor (AhR) protein before B[a]P exposure, assuming that this status enables the cells to respond to B[a]P more readily as well as more efficiently. B[a]P treatment resulted in the downregulation of AhR and induced cytochrome P450 1A1 (CYP1A1) (but not cytochrome P450 1B1 (CYP1B1)) expression and activity. While alpha-naphtoflavone (alpha-NF) and ellipticine suppressed B[a]P-induced CYP1A1 activation as well as apoptosis, the 2,3',4,5'-tetramethoxystilbene (TMS) and pyrene, known CYP1B1 inhibitors, failed to inhibit apoptosis. However, alpha-NF alone significantly increased CYP1A1 protein expression but not its activity, suggesting that alpha-NF more likely works as an AhR agonist in Hepa1c1c7 cells after B[a]P, rather than a direct inhibitor of CYP1A1 activity. In conclusion, it is suggested that the abundance of endogenous AhR level is an indispensable condition for an efficient cellular signaling of B[a]P and that control of AhR activity in Hepa1c1c7 cells might be important to cell fate resulting from CYP1A1 activation after B[a]P.
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