[en] This study unveils a novel cytochrome P450 (P450)-mediated metabolic pathway that drives cross-coupling between diverse phenol and arylamine pollutants. Phenols and arylamines constitute a large part of industrial chemicals, pharmaceuticals, and personal care products, yet the biotransformation of phenol-arylamine pollutant mixtures remains largely unexplored. Density functional theory calculations revealed that the rate-limiting rebound barriers of phenoxy and arylamino radicals formed through O-H/N-H abstraction by the P450 catalytic oxidant, Compound I, facilitate their dissociation from the heme, creating thermodynamically favorable conditions for subsequent nonrebound cross-coupling reactions. These proposed hybrid products were systematically identified and quantified using various mass spectrometry technologies across multiple biological systems, including human liver microsomes, recombinant human CYP3A4, mice, and zebrafish. From a physical organic chemistry perspective, the widespread occurrence of cross-coupling is driven by sufficient lifetime of phenoxy and arylamino radicals due to spin delocalization, and their concentration gradient sustained by persistent radical effects. Notably, yeast two-hybrid assays demonstrated that the phenol-arylamine hybrids exhibited supra-additive estrogenic activity; for instance, the bisphenol A-sulfamethoxazole dimer with a hydrolytic half-life of 11.6 days displayed approximately 130-fold higher estrogenic activity than that of bisphenol A. The mechanism's prevalence suggests an unrecognized bioactive pathway in chemical cocktails, thereby necessitating consideration of metabolism-driven reactive interactions in mixtures.
Disciplines :
Environmental sciences & ecology
Author, co-author :
Cheng, Shiyang; School of Environment and Spatial Informatics, China University of Mining and Technology, No. 1, Daxue Road, Xuzhou 221116, China
Jin, Lingmin; School of Environment and Spatial Informatics, China University of Mining and Technology, No. 1, Daxue Road, Xuzhou 221116, China
Ma, Juchen; School of Environment and Spatial Informatics, China University of Mining and Technology, No. 1, Daxue Road, Xuzhou 221116, China
Liu, Shun; School of Environment and Spatial Informatics, China University of Mining and Technology, No. 1, Daxue Road, Xuzhou 221116, China
Zhang, Shubin; Yunnan Key Laboratory of Forest Ecosystem Stability and Global Change, Xishuangbanna Tropical Botanical Garden, Chinese Academy of Sciences, Mengla 666303, China
Guan, Dong-Xing ; College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China
de Visser, Sam P ; Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom ; Department of Chemical Engineering, The University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
National Natural Science Foundation of China Key Laboratory of Pollution Exposure and Health Intervention of Zhejiang Province
Funding text :
This work was supported by the National Natural Science Foundation of China (Nos. 42361134581, 22176211, 22106168), and the Key Laboratory of Pollution Exposure and Health Intervention of Zhejiang Province (No. 20230008). We thank Prof. F. Peter Guengerich (Vanderbilt University School of Medicine) for his suggestions to improve the manuscript. This work is also dedicated to Prof. Rudi van Eldik (University of Erlangen-Nuremberg) on the occasion of his 80th birthday (August 8, 2025).
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