Elmorsy Ekramy, Al-Ghafari Ayat, Aggour Amal Misbah, Mosad Soaad Mohamed, Khan Raheela, Amer Saad
Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, Egypt.
Biochemistry Department, Faculty of Science, King Abdulaziz University (KAU), Jeddah, Saudi Arabia.
Toxicol Lett. 2017 Apr 15;272:94-100. doi: 10.1016/j.toxlet.2017.03.018. Epub 2017 Mar 18.
Antipsychotics (APs) are widely prescribed drugs, which are well known to cause reproductive adverse effects through mechanisms yet to be determined. The purpose of this study was to investigate the effect of antipsychotics on mitochondrial bioenergetics of rat ovarian theca cells as a possible mechanism of reproductive toxicity.
Isolated rat theca interstitial cells (TICs) were treated with two typical (chlorpromazine [CPZ] and haloperidol [HAL]) and two atypical APs (risperidone [RIS] and clozapine [CLZ]). The effects of these APs on TICs bioenergetics (ATP content, mitochondrial complexes I and III activities, oxygen consumption rates (OCRs), mitochondrial membrane potential (MPP) and lactate production) and on steroidogenesis (androstenedione and progesterone synthesis) were investigated.
All APs resulted in a concentration-dependent decrease in the ATP content of TICs. All APs at their estimated ICs (6μM, 21μM, 35μM and 37μM for CPZ, HAL, CLZ and RIS respectively) significantly decreased TICs OCRs (p<0.0001), MPP (p<0.0001) and significantly (p=0.0003) inhibited mitochondrial complex I activity. Only typical APs inhibited complex III (p=0.005). Also, APs at ICs increased TICs lactate production to varying degrees. All APs used at their ICs significantly inhibited progesterone (p=0.0022) and androstenedione (p=0.0027) production. Only CPZ was found to inhibit these hormones at the low concentration (1μM).
All four antipsychotics seem to inhibit mitochondrial bioenergetics and steroidogenesis in rat's ovarian theca cells. These findings support the hypothesis that APs-induced reproductive toxicity may be through mechanisms involving mitochondrial insult>. Further research is required to establish the link between APs-induced mitochondrial dysfunction and disordered steroidogenesis.
抗精神病药物（APs）是广泛使用的处方药，其通过尚未明确的机制导致生殖方面的不良反应这一点已广为人知。本研究的目的是探究抗精神病药物对大鼠卵巢膜细胞线粒体生物能量学的影响，以此作为生殖毒性的一种可能机制。
用两种典型抗精神病药物（氯丙嗪[CPZ]和氟哌啶醇[HAL]）以及两种非典型抗精神病药物（利培酮[RIS]和氯氮平[CLZ]）处理分离出的大鼠膜间质细胞（TICs）。研究这些抗精神病药物对TICs生物能量学（ATP含量、线粒体复合物I和III活性、氧消耗率[OCRs]、线粒体膜电位[MPP]和乳酸生成）以及对类固醇生成（雄烯二酮和孕酮合成）的影响。
所有抗精神病药物均导致TICs的ATP含量呈浓度依赖性下降。所有抗精神病药物在其估计的半数抑制浓度（IC，CPZ、HAL、CLZ和RIS分别为6μM、21μM、35μM和37μM）时均显著降低TICs的OCRs（p<0.0001）、MPP（p<0.0001），并显著（p=0.0003）抑制线粒体复合物I活性。只有典型抗精神病药物抑制复合物III（p=0.005）。此外，处于半数抑制浓度的抗精神病药物不同程度地增加了TICs的乳酸生成。所有处于半数抑制浓度使用的抗精神病药物均显著抑制孕酮（p=0.0022）和雄烯二酮（p=0.0027）的生成。仅发现CPZ在低浓度（1μM）时抑制这些激素。
所有四种抗精神病药物似乎都能抑制大鼠卵巢膜细胞的线粒体生物能量学和类固醇生成。这些发现支持了以下假设：抗精神病药物诱导的生殖毒性可能是通过涉及线粒体损伤的机制。需要进一步研究来确立抗精神病药物诱导的线粒体功能障碍与紊乱的类固醇生成之间的联系。
