Structural Identification of Diindole Agonists of the Aryl Hydrocarbon Receptor Derived from Degradation of Indole-3-pyruvic Acid

Abstract

Aerobic incubation of the tryptophan transamination/oxidation product indole-3-pyruvic acid (I3P) at pH 7.4 and 37 °C yielded products with activity as Ah receptor (AHR) agonists. The extracts were fractionated using HPLC and screened for AHR agonist activity. Two compounds were identified as agonists: 1,3-di(1H-indol-3-yl)propan-2-one (1) and 1-(1H-indol-3-yl)-3-(3H-indol-3-ylidene) propan-2-one (2), with the potency of 2 being 100-fold > 1 (Nguyen et al. (2009) Chem. Res. Toxicol. 22, xxx-xxx, accompanying paper). Both 1 and 2 showed UV spectra indicative of indole. The molecular formulae were established by high-resolution mass spectrometry (HRMS) and the structures were determined by a combination of NMR methods, including 1H, natural abundance 13C, and two-dimensional methods. An intermediate in the oxidation of I3P to 1 is 3-hydroxy-2,4-di(1H-indol-3-yl)butanal (HRMS established the presence of a compound with the formula C20H19N2O2). Compound 1 was converted to 2 in air or (faster) with mild oxidants, and 2 could be further oxidized to 1,3-di(3H-indol-3-ylidene)propan-2-one. Determination of the structures allowed estimation of the molar Ah receptor agonist activity of these natural products, similar in potency to known classical AHR inducers.

Aryl Hydrocarbon Receptor-Null Allele Mice Have Hematopoietic Stem/Progenitor Cells with Abnormal Characteristics and Functions

“…However, direct relationships between the modulation of known responsive genes and specific functional outcomes in cells/tissues have to be yet determined. Likewise, the normal function of the AhR is not known and true endogenous ligands have not been clearly identified, although recent data suggest likely candidates [7][8][9].…”

Fluorescence determination of d- and l-tryptophan concentrations in rat plasma following administration of tryptophan enantiomers using HPLC with pre-column derivatization

“…With regard to d-tryptophan (d-Trp), its several unique features have been reported. For example, d-Trp can be converted enzymatically to the corresponding ␣-keto acid, indole-3-pyruvic acid (I3P) by DAAO [6], and the generated I3P is dimerized by nonenzymatic condensation to produce 1,3-di(1H-indol-3-yl)propan-2-one and 1-(1H-indol-3-yl)-3-(3H-indol-3-ylidene)propan-2-one, which are able to function as an agonist for aryl hydrocarbon receptor [7]. d-Trp is also metabolized to d-kynurenine (d-KYN) [8][9][10], which is further converted to kynurenic acid (KYNA) by DAAO [11,12].…”

Induction of cytochrome P450 1 genes and stress response genes in developing zebrafish exposed to ultraviolet radiation

“…This appears to involve tryptophan, which has emerged as a prime candidate for formation of endogenous AHR agonists, via enzyme action or direct oxidation. Aspartate aminotransferase and D-amino acid oxidase form indole-3-pyruvate, which spontaneously oxidizes to diindole products able to activate the AHR at nanomolar concentrations (Bittinger et al 2003; Chowdhury et al 2009; Nguyen et al 2009). Oxidation of tryptophan by UV radiation or sunlight forms multiple products that can induce CYP1A gene expression (Diani-Moore et al 2006; Fritsche et al 2007; Mukai and Tischkau 2007).…”