Dairy cattle are predisposed to disease around the time of calving due to dysfunctional inflammatory responses. Oxylipids are lipid-derived mediators that regulate all aspects of the inflammatory response, and shifts in oxylipid profiles are correlated with disease risk. For example, 20-hydroxyeicosatetraenoic acid (HETE) is an oxylipid derived from cytochrome P450 enzymes (CYP450) found at significantly greater concentrations around calving and during clinical disease. Biosynthesis of 20-HETE occurs almost exclusively from two specific CYP450 of which CYP450 family four sub-family F member two (CYP4F2) is the major contributor to 20-HETE production in humans. To further study the activities of 20-HETE and potentially reduce its production in vivo, mitigation methods must be explored. Additional substrates of CYP4F2, such as vitamin E, are known to both increase and decrease the metabolism of other CYP4F2 substrates. This study aimed to determine whether vitamin E analogs may reduce the production of 20-HETE through competition for CYP4F2 activity in human CYP4F2, bovine-kidney and bovine-mammary microsomes. Gamma-tocopherol reduced 20-HETE production from human and bovine-kidney microsomes (35.3% and 27.5%, respectively) whereas γ-tocotrienol only reduced 20-HETE production from human microsomes (40.1%). Finally, bovine-mammary microsomes did not produce a quantifiable amount of 20-HETE, suggesting basal mammary CYP4F2 activity may not be a significant contributor to 20-HETE found in milk. Together, these data show that analogs of vitamin E can reduce the production of 20-HETE, potentially through competition with arachidonic acid for metabolism by CYP4F2, posing a potential means for limiting 20-HETE production during clinical diseases of dairy cattle.

中文翻译：

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维生素 E 类似物对人和牛细胞色素 P450 微粒体中 20-羟基二十碳四烯酸生物合成的抑制作用

由于功能失调的炎症反应，奶牛在产犊前后易患疾病。氧脂是调节炎症反应各个方面的脂质衍生介质，并且氧脂谱的变化与疾病风险相关。例如，20-羟基二十碳四烯酸 (HETE) 是一种衍生自细胞色素 P450 酶 (CYP450) 的氧脂，在产犊前后和临床疾病期间发现的浓度明显更高。20-HETE 的生物合成几乎完全来自两个特定的 CYP450，其中 CYP450 家族四亚家族 F 成员二 (CYP4F2) 是人类产生 20-HETE 的主要贡献者。为了进一步研究 20-HETE 的活性并可能减少其在体内的产生，必须探索缓解方法。CYP4F2 的其他底物，例如维生素 E，已知会增加和减少其他 CYP4F2 底物的代谢。本研究旨在确定维生素 E 类似物是否可以通过竞争人 CYP4F2、牛肾和牛乳腺微粒体中的 CYP4F2 活性来减少 20-HETE 的产生。γ-生育酚降低了人和牛肾微粒体的 20-HETE 产量（分别为 35.3% 和 27.5%），而 γ-生育三烯酚仅降低了人微粒体的 20-HETE 产量（40.1%）。最后，牛乳腺微粒体没有产生可量化的 20-HETE，这表明基础乳腺 CYP4F2 活性可能不是牛奶中发现的 20-HETE 的重要贡献者。总之，这些数据表明，维生素 E 的类似物可以减少 20-HETE 的产生，可能是通过与花生四烯酸竞争 CYP4F2 的代谢，