School of Pharmacy, Shujitsu University, Okayama, Japan;, Email:
School of Pharmacy, Shujitsu University, Okayama, Japan.
Pharmazie. 2021 Dec 5;76(12):611-613. doi: 10.1691/ph.2021.1836.
The objectives of this study were as follows: 1) to compare the metabolic activities of endogenous compounds and their effects on dopamine formation and hydroxylation of steroid hormones, mediated by human cytochrome P450 (CYP), including CYP2C9.1 and CYP2C19, as well as the variants CYP2C9.2 (Arg144Cys) and CYP2C9.3 (Ile359Leu); and 2) to assess the effects of steroid hormones on the activities of CYP2C9.1, CYP2C9.2, and CYP2C19 to estimate the contribution of the CYP2C subfamily to metabolism and drug-drug interactions of endogenous compounds. Dopamine formation from -tyramine and 6β- and 21- (for progesterone) hydroxylation of testosterone, cortisol, and progesterone by CYP2C9 variants, CYP2C19, CYP2D6, and CYP3A4 were determined using HPLC. The effects of steroid hormones such as testosterone, cortisol, and progesterone on tolbutamide methyl hydroxylation mediated by CYP2C subfamily members were investigated. Only CYP2D6 catalyzed dopamine formation. The 6β-hydroxylation activities of testosterone, cortisol, and progesterone catalyzed by CYP2C9 variants and CYP2D6 were less than 5% of those by CYP3A4. Although cortisol did not inhibit tolbutamide methyl hydroxylation catalyzed by CYP2C9.1, CYP2C9.2, or CYP2C19 and testosterone did not inhibit CYP2C19 activity, the reactions catalyzed by CY2C9.1 and CYP2C9.2 were inhibited by testosterone. The inhibition of progesterone by CYP2C19 was stronger than that by CYP2C9.1 and CYP2C9.2. CYP2C9.1 and CYP2C19 noncompetitively and competitively inhibited tolbutamide methyl hydroxylation with inhibition constants of 43.2 μM and 1.03 μM, respectively. Clinical interactions among endogenous compounds would vary within the CYP2C subfamily, although the contribution of the CYP2C subfamily may be of minor importance for dopamine formation and the detoxification (6β-hydroxylation) of endogenous steroid hormones.
1）比较内源性化合物的代谢活性及其对多巴胺形成和类固醇激素羟化的影响，这些影响由人细胞色素 P450（CYP）介导，包括 CYP2C9.1 和 CYP2C19 以及变体 CYP2C9.2（Arg144Cys）和 CYP2C9.3（Ile359Leu）；2）评估类固醇激素对 CYP2C9.1、CYP2C9.2 和 CYP2C19 活性的影响，以估计 CYP2C 亚家族对内源性化合物代谢和药物相互作用的贡献。使用 HPLC 测定 CYP2C9 变体、CYP2C19、CYP2D6 和 CYP3A4 介导的 -tyramine 转化为多巴胺和 6β-和 21-（用于孕酮）羟化睾酮、皮质醇和孕酮的活性。研究了类固醇激素如睾酮、皮质醇和孕酮对 CYP2C 亚家族成员介导的甲苯磺丁脲甲基羟化的影响。只有 CYP2D6 催化多巴胺形成。CYP2C9 变体和 CYP2D6 催化的睾酮、皮质醇和孕酮的 6β-羟化活性小于 CYP3A4 的 5%。虽然皮质醇不抑制 CYP2C9.1、CYP2C9.2 或 CYP2C19 介导的甲苯磺丁脲甲基羟化，但睾酮不抑制 CYP2C19 活性，但 CYP2C9.1 和 CYP2C9.2 的反应被睾酮抑制。孕酮对 CYP2C19 的抑制作用强于 CYP2C9.1 和 CYP2C9.2。CYP2C9.1 和 CYP2C19 以非竞争性和竞争性方式抑制甲苯磺丁脲甲基羟化，抑制常数分别为 43.2 μM 和 1.03 μM。尽管 CYP2C 亚家族对多巴胺形成和内源性类固醇激素的解毒（6β-羟化）可能意义不大，但内源性化合物之间的临床相互作用在 CYP2C 亚家族中会有所不同。
