Regioselective In Vitro Toxicity of Aromatic Hydroxylated Metabolites of 6PPD-Quinone

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6PPD-Q undergoes rapid enzymatic reactions within salmonids to form two major hydroxylated metabolites, one alkyl and one aryl. While alkyl-OH-6PPD-Q has been confirmed to be nontoxic, the toxicity of aryl-OH-6PPD-Q remains unknown. We herein synthesized three aryl-OH-6PPD-Q isomers and tested their in vitro toxicity in a coho salmon (O. kisutch) embryo (CSE-119) cell line. Para-aryl-OH-6PPD-Q was determined to be the isomer formed in vivo with comparable toxicity (EC50 = 5.4 µg/L) to parent 6PPD-Q. The toxicity of aryl-OH-6PPD-Q isomers is highly regioselective, with reduced toxicity observed for meta-aryl-OH-6PPD-Q (EC50 = 32.8 µg/L), while ortho-aryl-OH-6PPD-Q did not exhibit toxicity up to 100 µg/L. The structure-related toxicity trend of ortho- and para- aryl-OH-6PPD-Q was also observed for their methoxy analogues, demonstrating that the regioselective toxicity should not be attributed to the desolvation energy of -OH. Instead, DFT calculations suggest that the reduced toxicity of ortho-aryl-OH-6PPD-Q could be due to its relatively high torsional energy (7.1 kcal/mol) compared to other isomers. In summary, this study highlighted the regioselective toxicity of aryl-OH-6PPD-Q isomers, where steric repulsion and rotational restrictions could possibly play an important role.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.