The antioxidant N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and its oxidized quinone product 6PPD-quinone (6PPD-Q) in rubber have attracted attention due to the ecological risk that they pose. Both 6PPD and 6PPD-Q have been detected in various environments that humans cohabit. However, to date, a clear understanding of the biotransformation of 6PPD-Q and a potential biomarker for exposure in humans are lacking. To address this issue, this study presents a comprehensive analysis of the extensive biotransformation of 6PPD-Q across species, encompassing both in vitro and in vivo models. We have tentatively identified 17 biotransformation metabolites in vitro, 15 in mice in vivo, and confirmed the presence of two metabolites in human urine samples. Interestingly, different biotransformation patterns were observed across species. Through semiquantitative analysis based on peak areas, we found that almost all 6PPD-Q underwent biotransformation within 24 h of exposure in mice, primarily via hydroxylation and subsequent glucuronidation. This suggests a rapid metabolic processing of 6PPD-Q in mammals, underscoring the importance of identifying effective biomarkers for exposure. Notably, monohydroxy 6PPD-Q and 6PPD-Q-O-glucuronide were consistently the most predominant metabolites across our studies, highlighting monohydroxy 6PPD-Q as a potential key biomarker for epidemiological research. These findings represent the first comprehensive data set on 6PPD-Q biotransformation in mammalian systems, offering insights into the metabolic pathways involved and possible exposure biomarkers.

中文翻译：

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6PPD-醌的体外和体内生物转化分析及其在人尿液中的检测


橡胶中的抗氧化剂N-(1,3-二甲基丁基)-N'-苯基对苯二胺(6PPD)及其氧化醌产物6PPD-醌(6PPD-Q)因其带来的生态风险而引起人们的关注。 6PPD 和 6PPD-Q 均已在人类共同居住的各种环境中检测到。然而，迄今为止，人们对 6PPD-Q 的生物转化和人类暴露的潜在生物标志物还缺乏清晰的了解。为了解决这个问题，本研究对 6PPD-Q 跨物种的广泛生物转化进行了全面分析，包括体外和体内模型。我们在体外初步鉴定了 17 种生物转化代谢物，在小鼠体内鉴定了 15 种生物转化代谢物，并证实了人尿液样本中存在两种代谢物。有趣的是，不同物种观察到不同的生物转化模式。通过基于峰面积的半定量分析，我们发现几乎所有 6PPD-Q 在小鼠暴露后 24 小时内都发生了生物转化，主要是通过羟基化和随后的葡萄糖醛酸化。这表明哺乳动物中 6PPD-Q 的快速代谢过程，强调了识别有效暴露生物标志物的重要性。值得注意的是，单羟基 6PPD-Q 和 6PPD-Q-O-葡萄糖醛酸苷始终是我们研究中最主要的代谢物，突出显示单羟基 6PPD-Q 作为流行病学研究的潜在关键生物标志物。这些发现代表了哺乳动物系统中第一个关于 6PPD-Q 生物转化的综合数据集，提供了对所涉及的代谢途径和可能的暴露生物标志物的见解。