Microbial-derived 1,4-Dihydroxy-2-naphthoic acid and related compounds as aryl hydrocarbon receptor agonists/antagonists: Structure-activity relationships and receptor modeling

Yating Cheng, Un Ho Jin, Laurie A. Davidson, Robert S. Chapkin, Arul Jayaraman, Phanourios Tamamis, Asuka Orr, Clint Allred, Michael S. Denison, Anatoly Soshilov, Evelyn Weaver, Stephen Safe

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

1,4-Dihydroxy-2-naphthoic acid (1,4-DHNA) is a bacterial-derivedmetabolite that binds the aryl hydrocarbon receptor (AhR) and exhibits anti-inflammatory activity in the gut. The structure-dependent AhR activity of hydroxyl/carboxy-substituted naphthoic acids (NAs)was determined in young adultmouse colonic (YAMC) cells and human Caco2 colon cancer cells using CYP1A1/CYP1B1mRNAs asAh-responsive genes. Compounds used in this study include 1,4-, 3,5-, and 3,7-DHNA, 1,4- dimethoxy-2-naphthoic acid (1,4-DMNA), 1- and 4-hydroxy-2-naphthoic acid (1-HNA, 4-HNA), 1- and 2-naphthoic acid (1-NA, 2- NA), and 1- and 2-naphthol (1-NOH, 2-NOH). 1,4-DHNAwas themost potent compoundamong hydroxyl/carboxy naphthalene derivatives, and the fold induction response for CYP1A1 and CYP1B1was similar to that observed for 2,3,7,8-tetrachlorodibenzop- dioxin (TCDD) in YAMC and Caco2 cells. 1- and 4-HNAwere less potent than 1,4-DHNA but inducedmaximal (TCDD-like) response for CYP1B1 (both cell lines) and CYP1A1 (Caco2 cells).With the exception of 1- and 2-NA, all compounds significantly induced Cyp1b1 inYAMCcells and these responseswere not observed in AhR-deficient YAMC cells generated using CRISPR/ Cas9 technology. In addition,we also observed that 1- and 2-NOH(and 1,4-DHNA)wereweakAhR agonists, and 1- and 2-NOH also exhibited partialAhR antagonist activity. Structure-activity relationship studies for CYP1A1 but not CYP1B1were similar in both cell lines, and CYP1A1 induction required one or both 1,4-dihydroxy substituents and activitywas significantly enhanced by the 2-carboxyl group.We also used computational analysis to showthat 1,4-DHNAand TCDDshare similar interactions within the AhR binding pocket and differ primarily due to the negatively charged group of 1,4-DHNA.

Original languageEnglish (US)
Pages (from-to)458-473
Number of pages16
JournalToxicological Sciences
Volume155
Issue number2
DOIs
StatePublished - Feb 1 2017

Keywords

  • 1,4-DHNA
  • Agonists
  • Ah receptor
  • Antagonists
  • Structure-activity

ASJC Scopus subject areas

  • Toxicology

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    Cheng, Y., Jin, U. H., Davidson, L. A., Chapkin, R. S., Jayaraman, A., Tamamis, P., Orr, A., Allred, C., Denison, M. S., Soshilov, A., Weaver, E., & Safe, S. (2017). Microbial-derived 1,4-Dihydroxy-2-naphthoic acid and related compounds as aryl hydrocarbon receptor agonists/antagonists: Structure-activity relationships and receptor modeling. Toxicological Sciences, 155(2), 458-473. https://doi.org/10.1093/toxsci/kfw230