Metyrapone

Metyrapone is a potent oral 11β-hydroxylase inhibitor and autophagy activator that also inhibits aldosterone production. It can be used in the study of depression, atherosclerosis and cancer^[1,2].

Metyrapone (100μM; 2h) hyperactivates autophagy in HepG2, and delays the activation of apoptosis at severe endoplasmic reticulum (ER) stress^[3]. In H295R cells, treatment with Metyrapone (20μM; 48h) for 48 hours significantly reduced cortisol levels, which were 25.2±4.3μg/L in untreated cells and decreased to 18.9±0.3μg/L after Metyrapone treatment^[4].

Neuronal loss in the hippocampal CAl region was significantly reduced in the 4VO model in rats administered Metyrapone (200 mg/kg; sc; 30 min before ischaemia)^[5]. There was significant impairment of ovarian and uterine development in the young female Metyrapone-treated (100mg/kg; ip; 30d) mice with the incidence of corpora lutea being reduced 82%. Seminal vesicle and body weights were significantly reduced in juvenile males^[6]. Metyrapone (100mg/kg; ip; 4 weeks) treatment reduced the relative mRNA expression levels of phosphoenolpyruvate carboxykinase, a gluconeogenic GR target gene, in the liver and was associated with increased relative mRNA expression levels of the adrenal high-density lipoprotein receptor, SR-BI, and the steroidogenic enzymes, CYP11A1 and CYP11B^[7].

References:
[1]. Roozendaall B, Bohus B, McGaugh J L. Dose-dependent suppression of adrenocortical activity with metyrapone: effects on emotion and memory[J]. Psychoneuroendocrinology, 1996, 21(8): 681-693.
[2]. Jahn H, Schick M, Kiefer F, et al. Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial[J]. Archives of general psychiatry, 2004, 61(12): 1235-1244.
[3]. Holczer M, Márton M, Kurucz A, et al. A comprehensive systems biological study of autophagy‐apoptosis crosstalk during endoplasmic reticulum stress[J]. BioMed research international, 2015, 2015(1): 319589.
[4]. Germano A, Saba L, De Francia S, et al. CYP11B1 has no role in mitotane action and metabolism in adrenocortical carcinoma cells[J]. PloS one, 2018, 13(5): e0196931.
[5]. Lidhar N K, Darvish-Ghane S, Sivaselvachandran S, et al. Prelimbic cortex glucocorticoid receptors regulate the stress-mediated inhibition of pain contagion in male mice[J]. Neuropsychopharmacology, 2021, 46(6): 1183-1193.
[6]. Pasley J N, McKinney R D, Blue L R. Effects of metyrapone on reproductive organs of house mice[J]. Proceedings of the Society for Experimental Biology and Medicine, 1975, 148(2): 333-336.
[7]. van der Sluis R J, van den Aardweg T, Sijsenaar T J P, et al. Metyrapone Treatment Protects Low-Density Lipoprotein Receptor Knockout Mice against Hypercorticosteronemia Development without Changing Atherosclerosis Susceptibility[J]. Biomolecules, 2023, 13(9): 1287.

Metyrapone是一种强效的口服11β羟化酶抑制剂和自噬激活剂，还能抑制醛固酮的产生。Metyrapone可用于抑郁症、动脉粥样硬化和癌症的研究^[1,2]。

Metyrapone（100μM；2h）可激活HepG2细胞的自噬，并延迟严重内质网（ER）应激时细胞凋亡的激活^[3]。在H295R细胞中，用Metyrapone（20μM；48h）处理48小时可显著降低皮质醇水平，未处理细胞的皮质醇水平为25.2±4.3μg/L，Metyrapone处理后降至18.9±0.3μg/L^[4]。

在四血管阻断模型中，服用Metyrapone（200mg/kg；sc；30min before ischaemia）的大鼠海马CAl区的神经元丢失明显减少^[5]。经Metyrapone（100mg/kg；ip；30d）处理的年轻雌性小鼠的卵巢和子宫发育明显受损，黄体发生率降低了82%，幼年雄性小鼠的精囊和体重明显降低^[6]。Metyrapon（100mg/kg；ip；4 weeks）治疗降低了肝脏中磷酸烯醇丙酮酸羧激酶（一种葡萄糖生成 GR 的靶基因）的相对 mRNA 表达水平，并升高了肾上腺高密度脂蛋白受体SR-BI和类固醇生成酶CYP11A1和CYP11B的相对mRNA表达水平^[7]。