PMID- 10605936
OWN - NLM
STAT- MEDLINE
DCOM- 20000106
LR  - 20220318
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 59
IP  - 1
DP  - 2000 Jan 1
TI  - Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative 
      stress response, cell cycle control, and apoptosis.
PG  - 65-85
AB  - The chronology and history of characterizing the aromatic hydrocarbon [Ah] 
      battery is reviewed. This battery represents the Ah receptor (AHR)-mediated 
      control of at least six, and probably many more, dioxin-inducible genes; two 
      cytochrome P450 genes-P450 1A1 and 1A2 (Cypla1, Cypla2-and four non-P450 genes, 
      have experimentally been documented to be members of this battery. Metabolism of 
      endogenous and exogenous substrates by perhaps every P450 enzyme, but certainly 
      CYP1A1 and CYP1A2 (which are located, in part, in the mitochondrion), have been 
      shown to cause reactive oxygenated metabolite (ROM)-mediated oxidative stress. 
      Oxidative stress activates genes via the electrophile response element (EPRE) DNA 
      motif, whereas dioxin (acutely) activates genes via the AHR-mediated aromatic 
      hydrocarbon response element (AHRE) DNA motif. In contrast to dioxin, AHR ligands 
      that are readily metabolized to ROMs (e.g. benzo[a]pyrene, beta-naphthoflavone) 
      activate genes via both AHREs and the EPRE. The importance of the AHR in cell 
      cycle regulation and apoptosis has just begun to be realized. Current evidence 
      suggests that the CYP1A1 and CYP1A2 enzymes might control the level of the 
      putative endogenous ligand of the AHR, but that CYPA1/1A2 metabolism generates 
      ROM-mediated oxidative stress which can be ameliorated by the four non-P450 
      EPRE-driven genes in the [Ah] battery. Oxidative stress is a major signal in 
      precipitating apoptosis; however, the precise mechanism, or molecule, which 
      determines the cell's decision between apoptosis and continuation with the cell 
      cycle, remains to be elucidated. The total action of AHR and the [Ah] battery 
      genes therefore represents a pivotal upstream event in the apoptosis cascade, 
      providing an intricate balance between promoting and preventing ROM-mediated 
      oxidative stress. These proposed endogenous functions of the AHR and [Ah] enzymes 
      are, of course, in addition to the frequently described functions of "metabolic 
      potentiation" and "detoxification" of various foreign chemicals.
FAU - Nebert, D W
AU  - Nebert DW
AD  - Department of Environmental Health and the Center for Environmental Genetics, 
      University of Cincinnati Medical Center, OH 45267-0056, USA. dan.nebert@uc.edu
FAU - Roe, A L
AU  - Roe AL
FAU - Dieter, M Z
AU  - Dieter MZ
FAU - Solis, W A
AU  - Solis WA
FAU - Yang, Y
AU  - Yang Y
FAU - Dalton, T P
AU  - Dalton TP
LA  - eng
GR  - R01 AG09235/AG/NIA NIH HHS/United States
GR  - R01 ES06321/ES/NIEHS NIH HHS/United States
GR  - R01 ES08147/ES/NIEHS NIH HHS/United States
GR  - etc.
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PT  - Review
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 42HK56048U (Tyrosine)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Animals
MH  - Apoptosis/*physiology
MH  - Cell Cycle/*physiology
MH  - Glutathione/metabolism
MH  - Humans
MH  - Oxidative Stress/*physiology
MH  - Receptor Cross-Talk
MH  - Receptors, Aryl Hydrocarbon/*physiology
MH  - Signal Transduction
MH  - Tyrosine/metabolism
MH  - Tyrosinemias/metabolism
RF  - 199
EDAT- 1999/12/22 00:00
MHDA- 1999/12/22 00:01
CRDT- 1999/12/22 00:00
PHST- 1999/12/22 00:00 [pubmed]
PHST- 1999/12/22 00:01 [medline]
PHST- 1999/12/22 00:00 [entrez]
AID - S0006-2952(99)00310-X [pii]
AID - 10.1016/s0006-2952(99)00310-x [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2000 Jan 1;59(1):65-85. doi: 10.1016/s0006-2952(99)00310-x.