Connick J Patrick, Stepter Amari A, Cawley George F, Eyer Marilyn K, Backes Wayne L
Department of Pharmacology and Experimental Therapeutics, and The Stanley S. Scott Cancer Center, Louisiana State University Health Science Center, New Orleans, LA, United States.
Front Public Health. 2025 Jun 10;13:1531134. doi: 10.3389/fpubh.2025.1531134. eCollection 2025.
This study focuses on the effect of Environmentally Persistent Free Radicals (EPFRs) on the P450 enzymes of the CYP1 family. EPFRs are a component of particulate pollutants, that are stable in the environment, but can generate free radicals, leading to oxidative stress and subsequent toxicity of the respiratory, cardiovascular, and immune systems once they enter an organism. The results show differences in the ability of EPFRs to inhibit CYP1-dependent substrate metabolism, with CYP1B1 being inhibited to the greatest extent. There also were differences in the ability of EPFRs to disrupt the POR•CYP1 complex, with CYP1B1 being the only form where EPFRs disrupted POR•CYP1B1 complex formation. Despite the inhibition of substrate metabolism, each CYP1 enzyme, when reconstituted with NADPH-cytochrome P450 reductase (POR) was able to synergistically stimulate the generation of reactive oxygen (ROS) in the presence of particulate matter. Interestingly, both POR and the CYP1 enzymes were able to stimulate ROS generation, even when in partial reconstituted systems where only one of the proteins was present. However, when both POR and CYP1 were combined in a complete reconstituted system, ROS generation was synergistically stimulated.
本研究聚焦于环境持久性自由基（EPFRs）对CYP1家族P450酶的影响。EPFRs是颗粒污染物的一个组成部分，在环境中稳定，但能产生自由基，一旦进入生物体，会导致氧化应激以及随后呼吸系统、心血管系统和免疫系统的毒性。结果显示，EPFRs抑制CYP1依赖性底物代谢的能力存在差异，其中CYP1B1受到的抑制程度最大。EPFRs破坏POR•CYP1复合物的能力也存在差异，CYP1B1是EPFRs唯一能破坏POR•CYP1B1复合物形成的形式。尽管底物代谢受到抑制，但每种CYP1酶在与NADPH - 细胞色素P450还原酶（POR）重组时，在颗粒物存在的情况下能够协同刺激活性氧（ROS）的生成。有趣的是，即使在仅存在一种蛋白质的部分重组系统中，POR和CYP1酶都能够刺激ROS生成。然而，当POR和CYP1在完整的重组系统中结合时，ROS生成受到协同刺激。
