title: Abundance of aryl hydrocarbon receptor potentiates benzo[a]pyrene-induced apoptosis in Hepa1c1c7 cells via CYP1A1 activation.
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.
authors: Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Dongdaeshin-dong 3-1, Seo-gu, Busan 602-714, Republic of Korea.
authors: Jin-Yong
authors: JY
authors: Chung
authors: Ji Young
authors: JY
authors: Kim
authors: Won Rok
authors: WR
authors: Kim
authors: Seung Gee
authors: SG
authors: Lee
authors: Yoon-Jae
authors: YJ
authors: Kim
authors: Ji-Eun
authors: JE
authors: Park
authors: Yeon-Pyo
authors: YP
authors: Hong
authors: Young-Jin
authors: YJ
authors: Chun
authors: Young Chul
authors: YC
authors: Park
authors: Seunghoon
authors: S
authors: Oh
authors: Ki Soo
authors: KS
authors: Yoo
authors: Young Hyun
authors: YH
authors: Yoo
authors: Jong-Min
authors: JM
authors: Kim
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D001571:Benzoflavones / Q000494:pharmacology; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1; D015536:Down-Regulation; D004611:Ellipticines / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D001189:Aryl Hydrocarbon Hydroxylases; D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene; D001571:Benzoflavones; D002273:Carcinogens; D053148:Caspase 3; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D004611:Ellipticines; D004791:Enzyme Inhibitors; D018336:Receptors, Aryl Hydrocarbon; D016159:Tumor Suppressor Protein p53; C484722:Ahr protein, mouse; C034192:ellipticine; C011512:alpha-naphthoflavone; C585498:Cyp1b1 protein, mouse; C505409:Casp3 protein, mouse