This study was designed to characterize lauric acid metabolism to facilitate the establishment of cytochrome P450 4A11 (CYP4A11) inhibition assay. Three metabolites (2-, 11-, and 12-hydroxylauric acids) were identified in pooled human liver microsomes based on comparisons with authentic standards. Reaction phenotyping using 14 recombinant CYPs showed that ω-hydroxylation was mediated dominantly by CYP4A11 and marginally by CYP4F3B. CYP2B6 played an exclusive role in the formation of 2-hydroxylauric acid. The production of 11-hydroxylauric acid was mediated by CYP2E1, CYP2C9, CYP2B6, CYP1A2, CYP3A4, and CYP4A11. The IC₅₀ values of HET0016, a well-known pan-CYP4 inhibitor, against the formation of 12-, 11-, and 2-hydroxylauric acid were 1.0, 1.0, and 0.009 μM, respectively. Among the 50 natural compounds examined, plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) inhibited the formation of 12-, 11-, and 2-hydroxylauric acid with IC₅₀ values of 1.7, 2.3, and 2.7 μM, respectively. In the selectivity study, HET0016 inhibited CYP2B6 with an IC₅₀ of 9.2 nM, as well as CYP1A2, CYP2C19, and CYP2E1 with IC₅₀ values of 1–2 μM. Plumbagin inhibited all CYP enzymes tested with IC₅₀ values of 1.7–3.0 μM. These methods can be used as tools to develop CYP4A11 inhibitors; simultaneous determination of the hydroxylauric acid metabolites provides further information on selectivity.

本研究旨在表征月桂酸代谢，以促进细胞色素P450 4A11（CYP4A11）抑制测定的建立。根据与真实标准品的比较，在合并的人肝微粒体中鉴定出三种代谢物（2-，11-和12-羟基月桂酸）。使用14个重组CYP的反应表型显示ω-羟基化主要由CYP4A11介导，而少量由CYP4F3B介导。CYP2B6在2-羟基月桂酸的形成中起着排他性的作用。CYP2E1，CYP2C9，CYP2B6，CYP1A2，CYP3A4和CYP4A11介导11-羟基月桂酸的产生。IC ₅₀众所周知的泛CYP4抑制剂HET0016对抗12-，11-和2-羟基月桂酸形成的值分别为1.0、1.0和0.009μM。在所检查的50种天然化合物中，李白素（5-羟基-2-甲基-1,4-萘醌）抑制了12-，11-和2-羟基月桂酸的形成，IC ₅₀值为1.7、2.3和2.7μM ， 分别。在选择性研究中，HET0016抑制CYP2B6的IC ₅₀为9.2 nM，以及CYP1A2，CYP2C19和CYP2E1的IC ₅₀值为1-2μM。Plumbagin抑制所有用IC ₅₀测试的CYP酶值1.7–3.0μM。这些方法可用作开发CYP4A11抑制剂的工具。羟金酸代谢物的同时测定提供了关于选择性的进一步信息。