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Exposure to an Environmental Mixture of Polycyclic Aromatic Hydrocarbons Induces Hepatic Cytochrome P450 Enzymes in Mice
Chemical Research in Toxicology ( IF 4.1 ) Pub Date : 2021-09-02 , DOI: 10.1021/acs.chemrestox.1c00235
Ethan G Stoddard 1 , Subhasree Nag 1 , Jude Martin 1 , Kimberly J Tyrrell 1 , Teresa Gibbins 1 , Kim A Anderson 2 , Anil K Shukla 1 , Richard Corley 1 , Aaron T Wright 1, 3 , Jordan N Smith 1, 2
Affiliation  

Cytochrome P450 enzymes (CYPs) play an important role in bioactivating or detoxifying polycyclic aromatic hydrocarbons (PAHs), common environmental contaminants. While it is widely accepted that exposure to PAHs induces CYPs, effectively increasing rates of xenobiotic metabolism, dose- and time-response patterns of CYP induction are not well-known. In order to better understand dose- and time-response relationships of individual CYPs following induction, we exposed B6129SF1/J mice to single or repeated doses (2–180 μmol/kg/d) of benzo[a]pyrene (BaP) or Supermix-10, a mixture of the top 10 most abundant PAHs found at the Portland Harbor Superfund Site. In hepatic microsomes from exposed mice, we measured amounts of active CYPs using activity-based protein profiling and total CYP expression using global proteomics. We observed rapid Cyp1a1 induction after 6 h at the lowest PAH exposures and broad induction of many CYPs after 3 daily PAH doses at 72 h following the first dose. Using samples displaying Cyp1a1 induction, we observed significantly higher metabolic affinity for BaP metabolism (Km reduced 3-fold), 3-fold higher intrinsic clearance, but no changes to the Vmax. Mice dosed with the highest PAH exposures exhibited 1.7–5-fold higher intrinsic clearance rates for BaP compared to controls and higher Vmax values indicating greater amounts of enzymes capable of metabolizing BaP. This study demonstrates exposure to PAHs found at superfund sites induces enzymes in dose- and time-dependent patterns in mice. Accounting for specific changes in enzyme profiles, relative rates of PAH bioactivation and detoxification, and resulting risk will help translate internal dosimetry of animal models to humans and improve risk assessments of PAHs at superfund sites.

中文翻译:

暴露于多环芳烃的环境混合物会在小鼠中诱导肝细胞色素 P450 酶

细胞色素 P450 酶 (CYP) 在生物活化或解毒多环芳烃 (PAH)(常见的环境污染物)中发挥着重要作用。虽然人们普遍认为暴露于 PAHs 会诱导 CYPs,但有效增加外源代谢率、CYP 诱导的剂量和时间反应模式尚不为人所知。为了更好地了解诱导后单个 CYP 的剂量和时间反应关系,我们将 B6129SF1/J 小鼠暴露于单剂量或重复剂量(2-180 μmol/kg/d)苯并[ a] 芘 (BaP) 或 Supermix-10,是波特兰港超级基金现场发现的前 10 种最丰富多环芳烃的混合物。在来自暴露小鼠的肝微粒体中,我们使用基于活性的蛋白质分析测量了活性 CYP 的量,并使用全局蛋白质组学测量了总 CYP 表达。我们观察到在最低 PAH 暴露 6 小时后快速 Cyp1a1 诱导和在第一次给药后 72 小时每天 3 次 PAH 剂量后广泛诱导许多 CYP。使用显示 Cyp1a1 诱导的样品,我们观察到对 BaP 代谢的代谢亲和力显着提高(K m降低 3 倍),内在清除率提高 3 倍,但V max没有变化. 与对照组相比,给予最高 PAH 暴露剂量的小鼠对 BaP 的内在清除率高出 1.7-5 倍,而更高的V max值表明能够代谢 BaP 的酶量更大。这项研究表明,在超级基金站点发现的 PAH 暴露会在小鼠中以剂量和时间依赖性模式诱导酶。考虑到酶谱的具体变化、PAH 生物活化和解毒的相对速率以及由此产生的风险,将有助于将动物模型的内部剂量测定法转化为人类,并改进超级基金站点对 PAHs 的风险评估。
更新日期:2021-09-20
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