索拉非尼增加肝细胞癌患者细胞色素P450脂代谢物。
Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma.
发表日期：2023
作者：
Can G Leineweber, Miriam Rabehl, Anne Pietzner, Nadine Rohwer, Michael Rothe, Maciej Pech, Bruno Sangro, Rohini Sharma, Chris Verslype, Bristi Basu, Christian Sengel, Jens Ricke, Nils Helge Schebb, Karsten-H Weylandt, Julia Benckert
来源：
Experimental Hematology & Oncology
摘要：
肝细胞癌（HCC）是导致癌症死亡的主要原因，医疗治疗选择有限。多靶点激酶抑制剂索拉非尼是第一个广泛用于晚期HCC系统治疗的批准药物。索拉非尼可能影响多不饱和脂肪酸（PUFA）衍生的环氧化代谢物水平，因为它也是可溶性环氧酸水解酶（sEH）的强力抑制剂，sEH催化PUFA（如ω-6花生四烯酸（AA）和ω-3多巴酸（DHA））衍生的细胞色素P450（CYP）环氧代谢产物的转化为相应的二羟代谢物。AA衍生的环氧二十碳五烯酸（EET）的实验研究表明，它们可以促进肿瘤生长和转移，而DHA衍生的19,20-环氧二十二碳五烯酸（19,20-EDP）已经被证明在小鼠中具有抗肿瘤活性。在这项研究中，我们发现在接受索拉非尼治疗的43例HCC患者中，EET水平显著增加，19,20-EDP的水平趋势增加。我们证明，索拉非尼对CYP代谢物的影响导致19,20-EDP及其二羟代谢物的增加，而DHA血浆水平在索拉非尼治疗下降低。这些数据表明，特定补充DHA可用于增加具有潜在抗肿瘤活性的环氧化合物19,20-EDP的水平，在接受索拉非尼治疗的HCC患者中可能有重要作用。版权所有 ©2023 Leineweber、Rabehl、Pietzner、Rohwer、Rothe、Pech、Sangro、Sharma、Verslype、Basu、Sengel、Ricke、Schebb、Weylandt和Benckert。
Hepatocellular carcinoma (HCC) is a leading cause of cancer death, and medical treatment options are limited. The multikinase inhibitor sorafenib was the first approved drug widely used for systemic therapy in advanced HCC. Sorafenib might affect polyunsaturated fatty acids (PUFA)-derived epoxygenated metabolite levels, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of cytochrome-P450 (CYP)-derived epoxide metabolites derived from PUFA, such as omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding dihydroxy metabolites. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) have shown that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this study, we found a significant increase in EET levels in 43 HCC patients treated with sorafenib and a trend towards increased levels of DHA-derived 19,20-EDP. We demonstrate that the effect of sorafenib on CYP- metabolites led to an increase of 19,20-EDP and its dihydroxy metabolite, whereas DHA plasma levels decreased under sorafenib treatment. These data indicate that specific supplementation with DHA could be used to increase levels of the epoxy compound 19,20-EDP with potential anti-tumor activity in HCC patients receiving sorafenib therapy.Copyright © 2023 Leineweber, Rabehl, Pietzner, Rohwer, Rothe, Pech, Sangro, Sharma, Verslype, Basu, Sengel, Ricke, Schebb, Weylandt and Benckert.