Enantioselectivity in Metabolism and Toxicity of 6PPD-Quinone in Salmonids

作者：Rui Li, Holly Barrett, Pranav Nair, Minghua Wang, Haley Tomlin, Jamieson Atkinson, Erik T. Krogh, Lin-Na Xie, Hui Peng · 发表于：Environmental Science & Technology · 年份：2025 · DOI：10.1021/acs.est.4c12384 · 被引用次数：10 · 研究领域：Drug Transport and Resistance Mechanisms、Aquaculture disease management and microbiota、Bioactive Compounds and Antitumor Agents

The toxicity of N -(1,3-dimethylbutyl)- N ′-phenyl- p -phenylenediamine quinone (6PPD-Q) in salmonids has been found to be sensitive to even minor structural changes on its alkyl side chain. Inspired by this, we herein isolated the enantiomers of 6PPD-Q and tested their in vitro metabolism and toxicity in rainbow trout ( O. mykiss ) and coho salmon ( O. kisutch ). ( R )-6PPD-Q was found to be rapidly metabolized in rainbow trout liver S9 with a half-life ( t 1/2 ) of 11.4 min, which was 2.59 times faster than that of ( S )-6PPD-Q. Similarly, ( R )-6PPD-Q was preferentially metabolized in coho salmon liver S9. This was further evidenced by the preferential formation of an ( R )-aryl–OH-6PPD-Q metabolite. Supporting this, enantioselective accumulation of ( S )-6PPD-Q was found in rainbow trout in vivo . To further distinguish between kinetics and intrinsic toxicity, we tested the toxicity of 6PPD-Q enantiomers in the CSE-119 cell line with a minimal metabolism of 6PPD-Q. ( R )-6PPD-Q was found to strongly induce cytotoxicity in CSE-119 cells with a median effect concentration (EC 50 ) of 17.7 μg/L, which was 3.94 times stronger than that of ( S )-6PPD-Q. Likewise, ( R )-6PPD-Q was also the more toxic enantiomer in RTG-2 cells. In summary, this study reports the enantioselectivity of 6PPD-Q in both toxicity and metabolism.