title: Editor's Highlight: Microbial-Derived 1,4-Dihydroxy-2-naphthoic Acid and Related Compounds as Aryl Hydrocarbon Receptor Agonists/Antagonists: Structure-Activity Relationships and Receptor Modeling.
abstract: 1,4-Dihydroxy-2-naphthoic acid (1,4-DHNA) is a bacterial-derived metabolite 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 adult mouse colonic (YAMC) cells and human Caco2 colon cancer cells using CYP1A1/CYP1B1 mRNAs as Ah-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-DHNA was the most potent compound among hydroxyl/carboxy naphthalene derivatives, and the fold induction response for CYP1A1 and CYP1B1 was similar to that observed for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in YAMC and Caco2 cells. 1- and 4-HNA were less potent than 1,4-DHNA but induced maximal (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 in YAMC cells and these responses were 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) were weak AhR agonists, and 1- and 2-NOH also exhibited partial AhR antagonist activity. Structure-activity relationship studies for CYP1A1 but not CYP1B1 were similar in both cell lines, and CYP1A1 induction required one or both 1,4-dihydroxy substituents and activity was significantly enhanced by the 2-carboxyl group. We also used computational analysis to show that 1,4-DHNA and TCDD share similar interactions within the AhR binding pocket and differ primarily due to the negatively charged group of 1,4-DHNA.
authors.affiliation: Department of Veterinary Physiology and Pharmacology.
authors.forename: Yating
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Veterinary Physiology and Pharmacology.
authors.forename: Un-Ho
authors.initials: UH
authors.lastname: Jin
authors.affiliation: Department of Nutrition and Food Science.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Davidson
authors.affiliation: Department of Nutrition and Food Science.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Chapkin
authors.affiliation: Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, Texas 77843.
authors.forename: Arul
authors.initials: A
authors.lastname: Jayaraman
authors.affiliation: Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, Texas 77843.
authors.forename: Phanourios
authors.initials: P
authors.lastname: Tamamis
authors.affiliation: Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, Texas 77843.
authors.forename: Asuka
authors.initials: A
authors.lastname: Orr
authors.affiliation: Department of Nutrition and Food Science.
authors.forename: Clint
authors.initials: C
authors.lastname: Allred
authors.affiliation: Department of Environmental Toxicology, University of California, Davis, California 95616.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Denison
authors.affiliation: Department of Environmental Toxicology, University of California, Davis, California 95616.
authors.forename: Anatoly
authors.initials: A
authors.lastname: Soshilov
authors.affiliation: Department of Animal Science, Texas A&M University, College Station, Texas 77843.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Weaver
authors.affiliation: Department of Veterinary Physiology and Pharmacology ssafe@cvm.tamu.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1 / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D008962:Models, Theoretical; D009281:Naphthalenes / Q000633:toxicity; D009284:Naphthols / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D009281:Naphthalenes; D009284:Naphthols; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C024023:1,4-dihydroxy-2-naphthoic acid; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1
keywords: 1,4-DHNA; Ah receptor; agonists; antagonists.; structure-activity