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

© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. 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.