School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama, 703-8516, Japan.
Drug Metab Bioanal Lett. 2023;16(2):73-80. doi: 10.2174/2949681016666230830125358.
The inhibitory and stimulatory effects of several compounds, including steroid hormones and azole antifungal agents, on cortisol 6β-hydroxylation activity by cytochrome P450 (CYP) 3A4, polymorphically expressed CYP3A5, and fetal CYP3A7 were compared with those on testosterone 6β-hydroxylation to clarify the catalytic properties of the predominant forms of the human CYP3A subfamily.
6β-Hydroxylation activities of cortisol and testosterone by CYP3A4, CYP3A5, and CYP3A7 in the absence or presence of dehydroepiandrosterone (DHEA), α-naphthoflavone (ANF), ketoconazole, itraconazole, and voriconazole were measured using high-performance liquid chromatography.
Lower concentrations of DHEA and ANF increased cortisol 6β-hydroxylation activities catalyzed by CYP3A4 but not those catalyzed by CYP3A5 and CYP3A7. The inhibition strength of azole antifungal agents against cortisol 6β-hydroxylation catalyzed by all CYP3A subfamilies was similar to that of testosterone 6β-hydroxylation. Although the Michaelis constant () increased 2-fold in the presence of 20 μM DHEA compared to that of the control, the maximal velocity () values gradually increased with increasing DHEA. For ANF, both and values increased, although the value decreased at 2.5 μM concentrations. Ketoconazole and itraconazole competitively inhibited cortisol 6β-hydroxylation mediated by CYP3A4 with similar inhibition constants.
The inhibitory/stimulatory pattern among CYP3A subfamily members differed between cortisol and testosterone, and CYP3A4 was found to be the most sensitive in terms of inhibition by azole antifungals among the CYP3A subfamily members investigated.
比较几种化合物（包括甾体激素和唑类抗真菌药物）对细胞色素 P450（CYP）3A4、多态性表达的 CYP3A5 和胎儿 CYP3A7 催化皮质醇 6β-羟化活性的抑制和刺激作用，以及对睾酮 6β-羟化的作用，以阐明人 CYP3A 亚家族主要形式的催化特性。
使用高效液相色谱法测定 CYP3A4、CYP3A5 和 CYP3A7 缺乏或存在脱氢表雄酮（DHEA）、α-萘黄酮（ANF）、酮康唑、伊曲康唑和伏立康唑时皮质醇和睾酮的 6β-羟化活性。
较低浓度的 DHEA 和 ANF 增加了 CYP3A4 催化的皮质醇 6β-羟化活性，但不增加 CYP3A5 和 CYP3A7 催化的活性。唑类抗真菌药物对所有 CYP3A 亚家族催化的皮质醇 6β-羟化的抑制强度与睾酮 6β-羟化相似。虽然与对照相比，在 20μM DHEA 存在下，米氏常数（）增加了 2 倍，但值随着 DHEA 的增加而逐渐增加。对于 ANF，和值均增加，尽管在 2.5μM 浓度下值降低。酮康唑和伊曲康唑竞争性抑制 CYP3A4 介导的皮质醇 6β-羟化，抑制常数相似。
CYP3A 亚家族成员之间对皮质醇和睾酮的抑制/刺激模式不同，并且在所研究的 CYP3A 亚家族成员中，CYP3A4 被发现对唑类抗真菌药物的抑制最敏感。
