Characterizing the Metabolism of Tire Rubber-Derived <i>p</i>-Phenylenediamine Quinones to Identify Potential Exposure Biomarkers in Humans
Yingchen Yang, Wei Meng, Ya Zhang, Weikun Meng, J.Y. Li, Wei Liu, Guanyong Su
Abstract
There is growing evidence of the frequent detection of tire rubber-derived contaminants p -phenylenediamine-derived quinones (PPD-Qs) (e.g., highly toxic N -(1,3-dimethylbutyl)- N ′-phenyl- p -phenylenediamine quinone (6PPD-Q)) in the environment and biota and the adverse impact on organisms. Hence, a better understanding of their biotransformation/metabolism in humans is essential. However, relevant data are lacking owing to recent discoveries. Herein, the biotransformation patterns of 6PPD-Q and other five commonly detected PPD-Qs were characterized via combined in vitro assay and maternal cord blood screening monitoring. Rapid metabolism was found for each PPD-Q incubated with human liver S9 fraction and microsomes, resulting in the formation of abundant phase I and phase II metabolites. The subsequent screening for potential PPD-Q metabolites in blood samples showed the presence of suspect metabolites. Three detected metabolites were confirmed by matching the mass spectra and retention times of in vitro metabolites. N -Dealkylated, carboxy, carbonyl, and reductive metabolites and glucose, cysteine, and methionine conjugates were observed for the first time. The semiquantitative concentrations of metabolites were higher than those of the parent PPD-Qs, and several metabolites such as carboxy products were proposed as candidate biomarkers of PPD-Q exposure to humans. 6PPD-Q and N, N ′-diphenyl- p -phenylenediamine quinone were detected in maternal and/or cord whole blood samples for the first time. This study holds great importance in elucidating the potential risks and health effects of PPD-Qs.