Milczarek Ryszard, Sokołowska Ewa, Hallmann Anna, Kaletha Krystian, Klimek Jerzy
Department of Pharmaceutical Biochemistry, Medical University of Gdańsk, ul. Debinki 1, 80-211 Gdańsk, Poland.
J Steroid Biochem Mol Biol. 2008 Jun;110(3-5):230-5. doi: 10.1016/j.jsbmb.2007.11.004. Epub 2008 Apr 20.
During pregnancy placenta is the most significant source of lipid hydroperoxides and other reactive oxygen species (ROS). The increased production of lipid peroxides and other ROS is often linked to pre-eclampsia. It is already proved that placental endoplasmic reticulum may be an important place of lipid peroxides and superoxide radical production. In the present study we revealed that NADPH- and iron-dependent lipid peroxidation in human placental microsomes (HPM) inhibit placental aromatase--a key enzyme of estrogen biosynthesis in human placenta. We showed that significant inhibition of this enzyme is caused by small lipid peroxidation (TBARS (thiobarbituric acid-reactive substances)<4nmol/mg microsomal protein (m.p.)). More intensive lipid peroxidation (TBARS>9nmol/mg microsomal protein) diminishes aromatase activity to value being less than 5% of initial value. NADPH- and iron-dependent lipid peroxidation also causes disappearance of cytochrome P450 parallel to observed aromatase activity inhibition. EDTA, alpha-tocopherol, MgCl(2) and superoxide dismutase (SOD) prevent aromatase activity inhibition and cytochrome P450(AROM) degradation. Mannitol and catalase have not effect on TBARS synthesis, aromatase activity and cytochrome P450 degradation. In view of the above we postulate that the inhibition of aromatase activity observed is mainly a consequence of cytochrome P450(AROM) degradation induced by lipid radicals. The role of hydroxyl radical in cytochrome P450 degradation is negligible in our experimental conditions. The results presented here also suggest that the inhibition of aromatase activity can also take place in placenta at in vivo conditions.
在孕期，胎盘是脂质氢过氧化物和其他活性氧（ROS）的最重要来源。脂质过氧化物和其他ROS的产生增加通常与先兆子痫有关。已经证实，胎盘内质网可能是脂质过氧化物和超氧阴离子产生的重要场所。在本研究中，我们发现人胎盘微粒体（HPM）中NADPH和铁依赖性脂质过氧化会抑制胎盘芳香化酶——人胎盘雌激素生物合成的关键酶。我们发现，这种酶的显著抑制是由轻微脂质过氧化（硫代巴比妥酸反应性物质（TBARS）<4nmol/mg微粒体蛋白（m.p.））引起的。更强烈的脂质过氧化（TBARS>9nmol/mg微粒体蛋白）会使芳香化酶活性降低至初始值的5%以下。NADPH和铁依赖性脂质过氧化还会导致细胞色素P450消失，同时观察到芳香化酶活性受到抑制。乙二胺四乙酸（EDTA）、α-生育酚、氯化镁（MgCl₂）和超氧化物歧化酶（SOD）可防止芳香化酶活性受到抑制以及细胞色素P450（AROM）降解。甘露醇和过氧化氢酶对TBARS合成、芳香化酶活性和细胞色素P450降解没有影响。鉴于上述情况，我们推测观察到的芳香化酶活性抑制主要是脂质自由基诱导细胞色素P450（AROM）降解的结果。在我们的实验条件下，羟自由基在细胞色素P450降解中的作用可忽略不计。这里呈现的结果还表明，在体内条件下，胎盘也可能发生芳香化酶活性的抑制。
