Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic.
Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic.
Environ Toxicol Pharmacol. 2014 Nov;38(3):852-60. doi: 10.1016/j.etap.2014.10.004. Epub 2014 Oct 18.
17α-Ethinylestradiol (EE2) is an endocrine disruptor (ED) used as an ingredient of oral contraceptives. Rat hepatic microsomes metabolize EE2 to three products; two of them are hydroxylated EE2 derivatives. Of the hydroxylation reactions, 2-hydroxylation, is the major reaction. Cytochrome P450 (CYP) plays a major role in EE2 hydroxylation. To resolve which rat CYPs are responsible for EE2 oxidation, three approaches were used: induction of specific CYPs, selective inhibition of CYPs, and recombinant rat CYPs. The results demonstrate that EE2 is hydroxylated by several rat CYPs, among them CYP2C6 and 2C11 are most efficient in 2-hydroxy-EE2 formation, while CYP2A and 3A catalyze EE2 hydroxylation to the second product. EE2 is also an inhibitor of CYP2C- and CYP3A-catalyzed hydroxylation of endogenous EDs progesterone and testosterone. EE2 acts as a reversible inhibitor of CYP3A-mediated progesterone 6β-hydroxylation and inactivates CYP3A- and CYP2C-catalyzed testosterone 6β-hydroxylation and progesterone 21- or 16α-hydroxylation, respectively, in a mechanism-based manner.
17α-乙炔基雌二醇（EE2）是一种内分泌干扰物（ED），用作口服避孕药的成分。大鼠肝微粒体将 EE2 代谢为三种产物；其中两种是羟化 EE2 衍生物。在羟化反应中，2-羟化是主要反应。细胞色素 P450（CYP）在 EE2 羟化中起主要作用。为了解哪些大鼠 CYP 负责 EE2 氧化，采用了三种方法：特定 CYP 的诱导、CYP 的选择性抑制和重组大鼠 CYP。结果表明，几种大鼠 CYP 羟化 EE2，其中 CYP2C6 和 2C11 最有效地形成 2-羟-EE2，而 CYP2A 和 3A 催化 EE2 羟化生成第二种产物。EE2 也是 CYP2C 和 CYP3A 催化的内源性 ED 孕酮和睾酮羟化的抑制剂。EE2 可逆地抑制 CYP3A 介导的孕酮 6β-羟化，并以机制为基础分别使 CYP3A 和 CYP2C 催化的睾酮 6β-羟化和孕酮 21-或 16α-羟化失活。
