Technische Universität Kaiserslautern, Food Chemistry and Toxicology, Erwin-Schroedinger-Strasse 52, 67663, Kaiserslautern, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2020 Feb;393(2):213-223. doi: 10.1007/s00210-019-01724-0. Epub 2019 Sep 5.
Major metabolites of alpha-asarone in liver microsomes are epoxide-derived side-chain diols. The intermediately formed epoxides are mutagenic and form DNA adducts and thus are likely responsible for the (hepato) carcinogenic effect of alpha-asarone observed in male mice. We here investigated the role of eight human cytochrome P450 enzymes (CYP1A1, 1A2, 2A6, 2B6, 2C19, 2D6, 2E1, and 3A4) in the metabolism of alpha-asarone using Supersomes™. The epoxidation of the side-chain of alpha-asarone was mainly catalyzed by CYP3A4 and to a lesser extent by 2B6 and 1A1 whereas the hydroxylation of the side-chain leading to (E)-3'-hydroxyasarone was catalyzed by all investigated CYPs excluding CYP2A6. O-demethylation was catalyzed by CYP1A1, 2A6, 2B6, and 2C19. Applying relative activity factors (RAF) to the observed formation rates revealed that CYP3A4, at least at lower substrate concentrations, is nearly solely responsible for the formation of the mutagenic side-chain epoxides of alpha-asarone. Comparison of the RAF-corrected formation rates of all metabolites with those found in incubation with human liver microsomes revealed that the side-chain hydroxylation and epoxidation can be explained in good approximation by the tested hepatic CYPs, whereas other CYPs or enzymes may contribute to the O-demethylation of alpha-asarone. Therefore, the capacity for metabolic activation of alpha-asarone has to be expected to be widely present among the general population.
α-细辛脑在肝微粒体中的主要代谢物为环氧衍生的侧链二醇。中间形成的环氧化物具有致突变性，并形成 DNA 加合物，因此可能是雄性小鼠中观察到的 α-细辛脑（肝）致癌作用的原因。我们在这里使用 Supersomes™研究了 8 种人类细胞色素 P450 酶（CYP1A1、1A2、2A6、2B6、2C19、2D6、2E1 和 3A4）在 α-细辛脑代谢中的作用。α-细辛脑侧链的环氧化主要由 CYP3A4 催化，其次由 2B6 和 1A1 催化，而导致（E）-3'-羟基细辛脑的侧链羟化则由除 2A6 以外的所有研究 CYP 催化。O-去甲基化由 CYP1A1、2A6、2B6 和 2C19 催化。应用相对活性因子（RAF）来计算观察到的形成速率表明，CYP3A4 至少在较低的底物浓度下，几乎是 α-细辛脑形成致突变性侧链环氧化物的唯一原因。将所有代谢物的 RAF 校正形成速率与与人肝微粒体孵育时发现的速率进行比较表明，侧链羟化和环氧化可以很好地用测试的肝 CYP 来解释，而其他 CYP 或酶可能有助于 α-细辛脑的 O-去甲基化。因此，预计普遍存在代谢激活 α-细辛脑的能力。
