Microbial-derived 1,4-Dihydroxy-2-naphthoic acid and related compounds as aryl hydrocarbon receptor agonists/antagonists: Structure-activity relationships and receptor modeling
| Autor: | Cheng, Y, Jin, UH, Davidson, LA, Chapkin, RS, Jayaraman, A, Tamamis, P, Orr, A, Allred, C, Denison, MS, Soshilov, A, Weaver, E, Safe, S |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
antagonists
Polychlorinated Dibenzodioxins structure-activity Guinea Pigs 1 4-DHNA Naphthols Naphthalenes Models Theoretical Toxicology Cell Line Mice Structure-Activity Relationship Receptors Aryl Hydrocarbon Pharmacology And Pharmaceutical Sciences Ah receptor Cytochrome P-450 CYP1B1 Cytochrome P-450 CYP1A1 Animals Humans agonists Caco-2 Cells |
| Zdroj: | Cheng, Y; Jin, UH; Davidson, LA; Chapkin, RS; Jayaraman, A; Tamamis, P; et al.(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. doi: 10.1093/toxsci/kfw230. UC Office of the President: Research Grants Program Office (RGPO). Retrieved from: http://www.escholarship.org/uc/item/5ww3n1sh |
| DOI: | 10.1093/toxsci/kfw230. |
| Popis: | © 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. |
| Databáze: | OpenAIRE |
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