Agonistic effects of diverse xenobiotics on the constitutive androstane receptor as detected in a recombinant yeast-cell assay. (February 2018) - Kamata, Ryo
Abstract: The constitutive androstane receptor (CAR) is a nuclear receptor and transcription factor regulating proteins involved in xenobiotic metabolism. Agonist activation of the CAR can trigger metabolic activation and toxification as well as detoxification and clearance; accordingly, xenobiotic substances acting as CAR ligands may pose a threat to human and animal health. We used yeast cells transduced with the human CAR and the response pathway to measure the CAR-agonistic activities of 549 synthetic or natural compounds: 216 of the tested compounds exhibited CAR-agonistic effects. Eighty-four percent of CAR-activating compounds were aromatic compounds, and > 65% of these active compounds were aromatic hydrocarbons, bisphenols, monoalkyl phenols, phthalates, styrene dimers, diphenyl ethers, organochlorines, and organophosphates. The ten most potent compounds were 4- tert -octylphenol (4tOP; reference substance), 4-nonylphenol, diethylstilbestrol, benzyl n -butyl phthalate, 2-(4-hydroxyphenyl)-2, 4, 4-trimethylchroman, o, p′-DDT, methoxychlor, di- n -propyl phthalate, hexestrol, and octachlorostyrene. The activities of these nine non-reference compounds exceeded 10% of the 4tOP activity. Analysis of para -monoalkyl phenols suggests that branching of the alkyl group and chlorination at the ortho position raises potency. This study provides critical information for identifying the potential of CAR-mediated toxic hazards and for understanding the relevant mechanism. Highlights: 216 of 549 tested compounds agonistically activated the CAR. The majority of CAR-activating compounds were aromatic. Some monoalkyl phenols, phthalates, bisphenols, and organochlorines were potent. Branching and chlorination of para -monoalkyl phenols appeared to raise potency. All tested styrene dimers, but no styrene trimers, were active.