華南師范大學(xué)使用IPHASE肝微粒體在《Environment Pollution》上發(fā)表文章

近日，華南師范大學(xué)環(huán)境學(xué)院應(yīng)光國教授、趙建亮研究員團(tuán)隊2021級碩士研究生張源源等人在《Environment Pollution》上發(fā)表了題為“In vitro metabolism of the emerging contaminant 6PPD-quinone in human and rat liver microsomes: Kinetics, pathways, and mechanism”的論文（DOI: 10.1016/j.envpol.2024.123514，IF=8.9）。該研究使用IPHASE肝微粒體產(chǎn)品以體外代謝反應(yīng)體系探究了輪胎添加劑的抗氧化劑6PPD及其轉(zhuǎn)化產(chǎn)物6PPD醌（6PPD-Q）的I相代謝情況，通過疑似篩查和非靶向的分析方法闡明了可能的轉(zhuǎn)化產(chǎn)物及轉(zhuǎn)化路徑，結(jié)合表型分析實驗與分子對接明確了代謝6PPD-Q的關(guān)鍵作用酶。

發(fā)表于《Science》上論文之前報道了6PPD-Q對銀鮭魚的急性致死效應(yīng)，引起了世界范圍的廣泛關(guān)注，輪胎添加劑的安全性備受質(zhì)疑。6PPD-Q是橡膠抗氧化劑6PPD經(jīng)臭氧氧化的轉(zhuǎn)化產(chǎn)物，廣泛存在于各種環(huán)境介質(zhì)中，可通過吸入、食入和皮膚接觸等多種途徑進(jìn)入人體，進(jìn)而進(jìn)一步進(jìn)入人體的代謝系統(tǒng)。本研究以肝微粒體體外孵育體系探究6PPD和6PPD-Q的生物轉(zhuǎn)化情況，探討6PPD-Q對人體健康可能的影響。

此項研究結(jié)果表明研究6PPD-Q 在較低濃度下代謝顯著，但在高濃度下代謝程度降低。關(guān)鍵I 相代謝產(chǎn)物為單加氧和進(jìn)一步氧化的產(chǎn)物。與6PPD相比，6PPD-Q所需的代謝時間相對較長，代謝40 μg/L 6PPD的半衰期（t1/2）為28.9 min，而代謝16 μg/L 6PPD-Q的 t1/2則需要29.6 min，代謝80 μg/L 6PPD-Q的 t1/2則要達(dá)到254 min。這也說明與輪胎添加劑母體相比，轉(zhuǎn)化產(chǎn)物更難被人體所代謝，可能帶來更大的環(huán)境健康問題。未來的研究應(yīng)重點關(guān)注輪胎添加劑轉(zhuǎn)化產(chǎn)物，特別是其他PPD-Qs的轉(zhuǎn)化產(chǎn)物，以充分評估其對人類健康的影響。

摘    要

N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPD-Q) is an ozonation product of the rubber antioxidant N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD). 6PPD-Q has recently been detected in various environmental media, which may enter the human body via inhalation and skin contact pathways. However, the human metabolism of 6PPD-Q has remained unknown. This study investigated the in vitro Cytochrome P450-mediated metabolism of 6PPD-Q in human and rat liver microsomes (HLMs and RLMs). 6PPD-Q was significantly metabolized at lower concentrations but slowed at high concentrations. The intrinsic clearance (CLint) of 6PPD-Q was 21.10 and 18.58 μL min− 1 mg− 1 protein of HLMs and RLMs, respectively, suggesting low metabolic ability compared with other reported pollutants. Seven metabolites and one intermediate were identified, and metabolites were predicted immunotoxic or mutagenic toxicity. Mono- and di-oxygenation reactions were the main phase I in vitro metabolic pathways. Enzyme inhibition experiments and molecular docking techniques were further used to reveal the metabolic mechanism. CYP1A2, 3A4, and 2C19, especially 

CYP1A2, play critical roles in 6PPD-Q metabolism in HLMs, whereas 6PPD-Q is extensively metabolized in RLMs. Our study is the first to demonstrate the in vitro metabolic profile of 6PPD-Q in HLMs and RLMs. The results will significantly contribute to future human health management targeting the emerging pollutant 6PPD-Q.

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