PMID- 24161444
OWN - NLM
STAT- MEDLINE
DCOM- 20150106
LR  - 20211203
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 67
DP  - 2014 Feb
TI  - Methylated pentavalent arsenic metabolites are bifunctional inducers, as they 
      induce cytochrome P450 1A1 and NAD(P)H:quinone oxidoreductase through AhR- and 
      Nrf2-dependent mechanisms.
PG  - 171-87
LID - S0891-5849(13)01477-9 [pii]
LID - 10.1016/j.freeradbiomed.2013.10.810 [doi]
AB  - Activation of the aryl hydrocarbon receptor (AhR) ultimately leads to the 
      induction of the carcinogen-activating enzyme cytochrome P450 1A1 (CYP1A1), and 
      activation of the nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) in 
      addition to the AhR pathway induces the expression of the NADP(H):quinone 
      oxidoreductase (NQO1). Therefore, the aim of this study was to examine the effect 
      of As(III) pentavalent metabolites, MMA(V), DMA(V), and TMA(V), on AhR and Nrf2 
      activation and on the expression of their prototypical downstream targets CYP1A1 
      and NQO1, respectively. Our results showed that treatment of HepG2 cells with 
      MMA(V), DMA(V), or TMA(V) in the absence and presence of 
      2,3,7,8-tetrachlorodibenzo-p-dioxin or sulforaphane significantly induced both 
      CYP1A1 and NQO1 at the mRNA, protein, and catalytic activity levels. Furthermore, 
      these metabolites increased the AhR-dependent XRE-driven and the Nrf2-dependent 
      ARE-driven luciferase reporter activities, which coincided with increased nuclear 
      accumulation of both transcription factors. However, none of these metabolites 
      were shown to be AhR ligands. The induction of CYP1A1 by these metabolites seems 
      to be ligand-independent, possibly through a decrease in HSP90 protein expression 
      levels. The metabolites also increased ROS production, which was significantly 
      higher than that produced by As(III). Upon knockdown of AhR and Nrf2 the MMA(V)-, 
      DMA(V)-, and TMA(V)-mediated induction of both CYP1A1 and NQO1 proteins was 
      significantly decreased. In conclusion, this study demonstrates for the first 
      time that methylated pentavalent arsenic metabolites are bifunctional inducers, 
      as they increase CYP1A1 by activating the AhR/XRE signaling pathway and they 
      increase NQO1 by activating the Nrf2/ARE signaling pathway in addition to the 
      AhR/XRE pathway.
CI  - (c) 2013 Elsevier Inc. All rights reserved.
FAU - Anwar-Mohamed, Anwar
AU  - Anwar-Mohamed A
AD  - Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, 
      AB, Canada T6G 2E1.
FAU - Elshenawy, Osama H
AU  - Elshenawy OH
AD  - Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, 
      AB, Canada T6G 2E1.
FAU - Soshilov, Anatoly A
AU  - Soshilov AA
AD  - Department of Environmental Toxicology, University of California at Davis, Davis, 
      CA 95616, USA.
FAU - Denison, Michael S
AU  - Denison MS
AD  - Department of Environmental Toxicology, University of California at Davis, Davis, 
      CA 95616, USA.
FAU - Chris Le, X
AU  - Chris Le X
AD  - Analytical and Environmental Toxicology, Department of Laboratory Medicine and 
      Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, 
      AB, Canada T6G 2G3.
FAU - Klotz, Lars-Oliver
AU  - Klotz LO
AD  - Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, 
      AB, Canada T6G 2E1.
FAU - El-Kadi, Ayman O S
AU  - El-Kadi AO
AD  - Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, 
      AB, Canada T6G 2E1; College of Pharmacy, Qatar University, Doha 02713, Qatar. 
      Electronic address: aelkadi@ualberta.ca.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131024
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Arsenicals)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (Isothiocyanates)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Polychlorinated Dibenzodioxins)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (Sulfoxides)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 1.14.14.1 (CYP1A1 protein, human)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1A1)
RN  - EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone))
RN  - EC 1.6.5.2 (NQO1 protein, human)
RN  - GA49J4310U (sulforaphane)
SB  - IM
MH  - Antioxidant Response Elements
MH  - Arsenicals/*pharmacology
MH  - Cytochrome P-450 CYP1A1/*genetics/metabolism
MH  - Gene Expression Regulation
MH  - Genes, Reporter
MH  - HSP90 Heat-Shock Proteins/genetics/metabolism
MH  - Hep G2 Cells
MH  - Humans
MH  - Isothiocyanates/pharmacology
MH  - Luciferases/genetics/metabolism
MH  - Methylation
MH  - NAD(P)H Dehydrogenase (Quinone)/*genetics/metabolism
MH  - NF-E2-Related Factor 2/*genetics/metabolism
MH  - Polychlorinated Dibenzodioxins/pharmacology
MH  - Receptors, Aryl Hydrocarbon/*genetics/metabolism
MH  - Signal Transduction/*drug effects
MH  - Sulfoxides
OTO - NOTNLM
OT  - ARE
OT  - AhR
OT  - Arsenic
OT  - CYP1A1
OT  - Free radicals
OT  - NQO1
OT  - Nrf2
OT  - XRE
EDAT- 2013/10/29 06:00
MHDA- 2015/01/07 06:00
CRDT- 2013/10/29 06:00
PHST- 2013/06/03 00:00 [received]
PHST- 2013/09/29 00:00 [revised]
PHST- 2013/10/16 00:00 [accepted]
PHST- 2013/10/29 06:00 [entrez]
PHST- 2013/10/29 06:00 [pubmed]
PHST- 2015/01/07 06:00 [medline]
AID - S0891-5849(13)01477-9 [pii]
AID - 10.1016/j.freeradbiomed.2013.10.810 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2014 Feb;67:171-87. doi: 
      10.1016/j.freeradbiomed.2013.10.810. Epub 2013 Oct 24.