Shiyang Cheng, Lingmin Jin, Juchen Ma, Shun Liu, Shubin Zhang, Dong-Xing Guan, Sam P. de Visser, Emma L. Schymanski, Li Ji
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引用次数: 0
Abstract
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.
期刊介绍:
Environmental Science & Technology (ES&T) is a co-sponsored academic and technical magazine by the Hubei Provincial Environmental Protection Bureau and the Hubei Provincial Academy of Environmental Sciences.
Environmental Science & Technology (ES&T) holds the status of Chinese core journals, scientific papers source journals of China, Chinese Science Citation Database source journals, and Chinese Academic Journal Comprehensive Evaluation Database source journals. This publication focuses on the academic field of environmental protection, featuring articles related to environmental protection and technical advancements.