PMID- 15001395
OWN - NLM
STAT- MEDLINE
DCOM- 20040409
LR  - 20161019
IS  - 0003-9861 (Print)
IS  - 0003-9861 (Linking)
VI  - 423
IP  - 2
DP  - 2004 Mar 15
TI  - Aryl hydrocarbon receptor response to indigoids in vitro and in vivo.
PG  - 309-16
AB  - Indigo and indirubin have been reported to be present at low levels in human 
      urine. The possibility that indigoids are physiological ligands of the aryl 
      hydrocarbon receptor (AhR) has been suggested by initial studies in yeast, where 
      indirubin was found to be 50 times more potent than 
      2,3,7,8-tetrachlorodibenzo[p]dioxin (TCDD), and indigo was found to be 
      equipotent. To demonstrate that these indigoids are bona fide agonists in 
      mammalian systems, we employed a number of in vitro and in vivo measures of AhR 
      agonist potency. In a hepatoma cell reporter system, indigo yielded an EC50 of 
      approximately 5x10(-6)M (indirubin 3' -oxime EC50 approximately 5x10(-7)M, 
      indirubin EC50 approximately 1x10(-7)M). A comparison of these EC50 values with 
      that of 2,3,7,8-tetrachlorodibenzofuran (TCDBF) ( approximately 3x10(-9)M) 
      indicated that these compounds are less potent than classic 
      halogenated-dibenzofurans or -dibenzo-p-dioxins. Competitive binding assays for 
      AhR occupancy showed similar IC50 values for indirubin and TCDBF ( approximately 
      2x10(-9) and 5x10(-9)M), with the IC50 values of indigo and indirubin 3' -oxime 
      being approximately 10-fold higher. When rats were treated with these indigoids 
      in the range of 1.5-50mg/kg, induction of hepatic cytochrome P450 1A1 was 
      detected. Differences in the rank-order of potency observed in vivo and in vitro 
      could, in part, be explained by metabolism. Although their biological potencies 
      are not as high as has been previously suggested, collectively the results show 
      that these indole-derived pigments are agonists of AhR in vivo. The in vivo 
      results suggest that solubility, distribution, and metabolism influence the 
      response to the compounds.
FAU - Peter Guengerich, F
AU  - Peter Guengerich F
AD  - Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt 
      University School of Medicine, 638 Robinson Research Building, 23rd and Pierce 
      Avenues, Nashville, TN 37232-0146, USA. g.guengerich@vanderbilt.edu
FAU - Martin, Martha V
AU  - Martin MV
FAU - McCormick, W Andrew
AU  - McCormick WA
FAU - Nguyen, Linh P
AU  - Nguyen LP
FAU - Glover, Edward
AU  - Glover E
FAU - Bradfield, Christopher A
AU  - Bradfield CA
LA  - eng
GR  - R01 ES005703/ES/NIEHS NIH HHS/United States
GR  - P30 ES00267/ES/NIEHS NIH HHS/United States
GR  - R01 CA90426/CA/NCI NIH HHS/United States
GR  - R37 ES05703/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Arch Biochem Biophys
JT  - Archives of biochemistry and biophysics
JID - 0372430
RN  - 0 (Dioxins)
RN  - 0 (Indoles)
RN  - 0 (Oximes)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (indirubin-3'-monoxime)
RN  - D3741U8K7L (Indigo Carmine)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1A1)
RN  - V86L8P74GI (indirubin)
SB  - IM
MH  - Animals
MH  - Binding, Competitive
MH  - Cell Line, Tumor
MH  - Cytochrome P-450 CYP1A1/genetics/metabolism
MH  - Cytosol/metabolism
MH  - Dioxins/pharmacology
MH  - Humans
MH  - Indigo Carmine
MH  - Indoles/chemistry/metabolism/*pharmacology
MH  - Luciferases/genetics/metabolism
MH  - Male
MH  - Mice
MH  - Microsomes, Liver/metabolism
MH  - Oxidation-Reduction
MH  - Oximes/chemistry/metabolism/*pharmacology
MH  - Radioligand Assay
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Aryl Hydrocarbon/*agonists/*metabolism
MH  - Response Elements/genetics
MH  - Transfection
EDAT- 2004/03/06 05:00
MHDA- 2004/04/10 05:00
CRDT- 2004/03/06 05:00
PHST- 2003/12/17 00:00 [received]
PHST- 2004/01/07 00:00 [revised]
PHST- 2004/03/06 05:00 [pubmed]
PHST- 2004/04/10 05:00 [medline]
PHST- 2004/03/06 05:00 [entrez]
AID - S0003986104000049 [pii]
AID - 10.1016/j.abb.2004.01.002 [doi]
PST - ppublish
SO  - Arch Biochem Biophys. 2004 Mar 15;423(2):309-16. doi: 10.1016/j.abb.2004.01.002.