Characterizing\nthe Metabolism of Tire Rubber-Derived <i>p</i>‑Phenylenediamine\nQuinones to Identify Potential\nExposure Biomarkers in Humans

There is growing evidence of the\nfrequent detection of tire rubber-derived\ncontaminants <i>p</i>-phenylenediamine-derived quinones\n(PPD-Qs) (e.g., highly toxic <i>N</i>-(1,3-dimethylbutyl)-<i>N</i>′-phenyl-<i>p</i>-phenylenediamine quinone\n(6PPD-Q)) in the environment and biota and the adverse impact on organisms.\nHence, a better understanding of their biotransformation/metabolism\nin humans is essential. However, relevant data are lacking owing to\nrecent discoveries. Herein, the biotransformation patterns of 6PPD-Q\nand other five commonly detected PPD-Qs were characterized via combined\nin vitro assay and maternal cord blood screening monitoring. Rapid\nmetabolism was found for each PPD-Q incubated with human liver S9\nfraction and microsomes, resulting in the formation of abundant phase\nI and phase II metabolites. The subsequent screening for potential\nPPD-Q metabolites in blood samples showed the presence of suspect\nmetabolites. Three detected metabolites were confirmed by matching\nthe mass spectra and retention times of in vitro metabolites. <i>N</i>-Dealkylated, carboxy, carbonyl, and reductive metabolites\nand glucose, cysteine, and methionine conjugates were observed for\nthe first time. The semiquantitative concentrations of metabolites\nwere higher than those of the parent PPD-Qs, and several metabolites\nsuch as carboxy products were proposed as candidate biomarkers of\nPPD-Q exposure to humans. 6PPD-Q and <i>N</i>,<i>N</i>′-diphenyl-<i>p</i>-phenylenediamine quinone were\ndetected in maternal and/or cord whole blood samples for the first\ntime. This study holds great importance in elucidating the potential\nrisks and health effects of PPD-Qs.