Widespread occurrence of two typical N, N'-substituted p-phenylenediamines and their quinones in humans: Association with oxidative stress and liver damage

Abstract

While N, N'-substituted p-phenylenediamines (PPDs) and their quinone derivatives (PPDQs) have been widely detected in the environment, there is currently limited data on their occurrence in humans. In this study, we conducted the first serum analysis of two PPDs and PPDQs in the healthy and secondary nonalcoholic fatty liver disease (S-NAFLD) cohorts in South China. The concentrations of four oxidative stress biomarkers (OSBs), namely, 8-iso-prostaglandin F_2α (8-PGF_2α), 11β-prostaglandin F_2α (11-PGF_2α), 15(R)-prostaglandin F_2α (15-PGF_2α), and 8-hydroxy-2'-deoxyguanosine in serum samples were also measured. Results showed that N-(1,3-dimethybutyl)-N'-phenyl-p-phenylenediamine (6PPD) quinone was the predominant target analytes both in the healthy and S-NAFLD cohorts, with the median concentrations of 0.13 and 0.20 ng/mL, respectively. Significant (p < 0.05) and positive correlations were found between 6PPD concentration and 8-PGF_2α, 11-PGF_2α, and 15-PGF_2α in both the healthy and S-NAFLD cohorts, indicating that 6PPD may be associated with lipid oxidative damage. In addition, concentrations of 6PPD in serum were associated significantly linked with total bilirubin (β = 0.180 μmol/L, 95%CI: 0.036-0.396) and direct bilirubin (DBIL, β = 0.321 μmol/L, 95%CI: 0.035-0.677) related to hepatotoxicity. Furthermore, 8-PGF_2α, 11-PGF_2α, and 15-PGF_2α mediated 17.1%, 24.5%, and 16.6% of 6PPD-associated DBIL elevations, respectively. Conclusively, this study provides novel insights into human exposure to and hepatotoxicity assessment of PPDs and PPDQs.

Keywords: Liver damage; N; N’-substituted p-phenylenediamines; Oxidative stress; Quinone derivative.