Klimek J, Woźniak M, Szymańska G, Zelewski L
Department of Biochemistry, Medical University of Gdańsk, Poland.
Free Radic Biol Med. 1998 May;24(7-8):1168-75. doi: 10.1016/s0891-5849(97)00442-5.
Different natural and synthetic organic hydroperoxides have been found to stimulate TBARS formation in human term placental mitochondria. The levels of TBARS were lower than arising from NADPH-dependent lipid peroxidation. BHT, Mn2+ and DMPO counteracted TBARS formation in the presence of cumene hydroperoxide implicating involvement of free radicals in this process. On the other hand superoxide dismutase, catalase and EDTA while being inhibitory in NADPH-dependent lipid peroxidation did not inhibit cumene hydroperoxide-dependent TBARS formation. Amphenone B and SKF-525A, inhibitors of cytochrome P-450, strongly inhibit both NADPH- and cumene hydroperoxide-dependent lipid peroxidation. These data provide evidence that cytochrome P-450SCC is involved in both these processes. However NADPH-dependent lipid peroxidation and the cumene hydroperoxide have been found to inactivate placental mitochondrial cytochrome P-450SCC. The presence of cumene hydroperoxide resulted in a more rapid inactivation of cytochrome P-450SCC and consequently inhibited NADPH-dependent lipid peroxidation. It has been observed for the first time that progesterone biosynthesis can be inhibited by cumene hydroperoxide. Protective effect of Mn2+ and DMPO on progesterone biosynthesis indicates the importance of free radicals as transient products of cytochrome P-450SCC-dependent cumene hydroperoxide metabolism. In contrast to progesterone formation from cholesterol, the conversion of pregnenolone to progesterone was not affected by cumene hydroperoxide. This suggests that inhibition of progesterone synthesis from cholesterol by hydroperoxide may be ascribed to its effect on the desmolase activity of cytochrome P-450SCC in placental mitochondria. On the basis of the results obtained, we propose that the inhibition of progesterone biosynthesis by naturally occurring hydroperoxides may contribute to the development of preeclampsia.
已发现不同的天然和合成有机氢过氧化物可刺激人足月胎盘线粒体中硫代巴比妥酸反应物（TBARS）的形成。TBARS的水平低于由NADPH依赖性脂质过氧化产生的水平。在存在异丙苯过氧化氢的情况下，丁基羟基甲苯（BHT）、锰离子（Mn2+）和5,5-二甲基-1-吡咯啉-N-氧化物（DMPO）可抵消TBARS的形成，这表明自由基参与了此过程。另一方面，超氧化物歧化酶、过氧化氢酶和乙二胺四乙酸（EDTA）虽然对NADPH依赖性脂质过氧化有抑制作用，但并未抑制异丙苯过氧化氢依赖性TBARS的形成。细胞色素P-450抑制剂安非他明B和SKF-525A强烈抑制NADPH和异丙苯过氧化氢依赖性脂质过氧化。这些数据证明细胞色素P-450侧链裂解酶（P-450SCC）参与了这两个过程。然而，已发现NADPH依赖性脂质过氧化和异丙苯过氧化氢会使胎盘线粒体细胞色素P-450SCC失活。异丙苯过氧化氢的存在导致细胞色素P-450SCC更快失活，从而抑制了NADPH依赖性脂质过氧化。首次观察到异丙苯过氧化氢可抑制孕酮的生物合成。锰离子和DMPO对孕酮生物合成的保护作用表明自由基作为细胞色素P-450SCC依赖性异丙苯过氧化氢代谢的瞬时产物的重要性。与由胆固醇形成孕酮不同，孕烯醇酮向孕酮的转化不受异丙苯过氧化氢的影响。这表明过氧化氢对胆固醇合成孕酮的抑制作用可能归因于其对胎盘线粒体中细胞色素P-450SCC的裂解酶活性的影响。根据所得结果，我们提出天然存在的氢过氧化物对孕酮生物合成的抑制作用可能导致先兆子痫的发展。
