PMID- 20051482
OWN - NLM
STAT- MEDLINE
DCOM- 20100422
LR  - 20240317
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 333
IP  - 1
DP  - 2010 Apr
TI  - Persistent induction of cytochrome P4501A1 in human hepatoma cells by 
      3-methylcholanthrene: evidence for sustained transcriptional activation of the 
      CYP1A1 promoter.
PG  - 99-109
LID - 10.1124/jpet.109.162222 [doi]
AB  - Cytochrome P450 (P450)1A1 plays a critical role in the metabolic activation and 
      detoxification of polycyclic aromatic hydrocarbons (PAHs), many of which are 
      potent human carcinogens. In this investigation, we tested the hypothesis that MC 
      elicits persistent induction of CYP1A1 expression in human hepatoma cells (HepG2) 
      and that this phenomenon is mediated by sustained transcriptional activation of 
      the CYP1A1 promoter. Treatment of HepG2 cells with MC resulted in marked 
      induction (8-20-fold) of ethoxyresorufin O-de-ethylase activities, CYP1A1 
      apoprotein contents, and mRNA levels, which persisted for up to 96 h. MC also 
      caused sustained transcriptional activation of the human CYP1A1 promoter for up 
      to 96 h, as inferred from transient transfection experiments. Experiments with 
      deletion constructs indicated that Ah response elements located at -886, -974, 
      and -1047, but not -491, nucleotides from the start site, contributed to the 
      sustained transcriptional activation of the CYP1A1 promoter. Electrophoretic 
      mobility-shift and chromatin immunoprecipitation assays suggested that prolonged 
      CYP1A1 induction was mediated by Ah receptor (AHR)-independent mechanisms. 
      Experiments with [3H]MC and liquid chromatography-tandem mass spectrometry 
      demonstrated rapid elimination of MC and its metabolites from the cells by 12 to 
      24 h, suggesting that these compounds did not elicit sustained CYP1A1 induction 
      via the classical AHR-mediated pathway. In conclusion, the results of this study 
      support the hypothesis that MC causes persistent induction of CYP1A1 in human 
      hepatoma cells by mechanisms entailing sustained transcriptional activation of 
      the CYP1A1 promoter via AHR-independent mechanisms. These observations have 
      important implications for human carcinogenesis mediated by PAHs.
FAU - Fazili, Inayat S
AU  - Fazili IS
AD  - Departments of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Jiang, Weiwu
AU  - Jiang W
FAU - Wang, Lihua
AU  - Wang L
FAU - Felix, Edward A
AU  - Felix EA
FAU - Khatlani, Tanvir
AU  - Khatlani T
FAU - Coumoul, Xavier
AU  - Coumoul X
FAU - Barouki, Robert
AU  - Barouki R
FAU - Moorthy, Bhagavatula
AU  - Moorthy B
LA  - eng
GR  - R01 ES009132/ES/NIEHS NIH HHS/United States
GR  - R01-ES009132-08/08S1/ES/NIEHS NIH HHS/United States
GR  - R01 HL087174/HL/NHLBI NIH HHS/United States
GR  - R01-HL087174/HL/NHLBI NIH HHS/United States
GR  - R01-HL070921/HL/NHLBI NIH HHS/United States
GR  - R01 HL070921/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20100105
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Carcinogens)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 56-49-5 (Methylcholanthrene)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1A1)
SB  - IM
MH  - Carcinogens/*toxicity
MH  - Cell Line, Tumor
MH  - Cytochrome P-450 CYP1A1/*biosynthesis/genetics
MH  - Humans
MH  - Methylcholanthrene/*toxicity
MH  - Promoter Regions, Genetic
MH  - RNA, Messenger/biosynthesis
MH  - Receptors, Aryl Hydrocarbon/physiology
MH  - Transcriptional Activation
PMC - PMC2846024
EDAT- 2010/01/07 06:00
MHDA- 2010/04/23 06:00
PMCR- 2011/04/01
CRDT- 2010/01/07 06:00
PHST- 2010/01/07 06:00 [entrez]
PHST- 2010/01/07 06:00 [pubmed]
PHST- 2010/04/23 06:00 [medline]
PHST- 2011/04/01 00:00 [pmc-release]
AID - jpet.109.162222 [pii]
AID - 3568304 [pii]
AID - 10.1124/jpet.109.162222 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2010 Apr;333(1):99-109. doi: 10.1124/jpet.109.162222. Epub 
      2010 Jan 5.