Reactivities and products of free radical oxidation of cholestadienols.
Reactivities and products of free radical oxidation of cholestadienols.
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DOI：
10.1021/ja5011674
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发表时间：
2014-04-09
影响因子：
15
通讯作者：
Porter NA
中科院分区：
文献类型：
--
作者：
Xu L;Porter NA
7-脱氢胆固醇（7-DHC）是迄今为止报道的最易氧化的脂质分子，其自由基过氧化的传播速率常数是胆固醇的200倍。为了更好地理解7-DHC的高反应性并阐明反应机理，我们合成了共轭和跳跃的非共轭胆甾二烯醇，这将给出7-DHC过氧化反应中形成的两个假定的胆甾烯基中间体之一。另外的二烯醇包括6，8（9）-二烯醇、5，8（14）-二烯醇、6，8（14）-二烯醇和生物学上重要的8-脱氢胆固醇（8-DHC; 5，8（9）-二烯醇）。我们发现，所有的二烯醇都比胆固醇的反应性显著（至少40倍）。其中，导致在甾醇的环B中形成α自由基（称为内-B）的二烯醇比导致跨越环B和C的α自由基（称为外-B）的那些二烯醇更具反应性。通过比较由7-DHC形成的氧甾醇谱和由8-DHC和5，8（14）-二烯醇形成的氧甾醇谱，由C-9和C-14处的氢原子的提取（H-9或H-14机理）形成的产物被清楚地区分。当在良好的氢原子供体α-生育酚存在下进行氧化时，7-DHC过氧化的氧固醇谱与不存在抗氧化剂时观察到的谱明显不同，并且更接近于在生物系统中观察到的谱。这项研究表明，氧化应激和氧化甾醇的积累应被认为是胆固醇生物合成或代谢障碍的两个关键因素，其中二烯基甾醇中间体的积累。
7-Dehydrocholesterol (7-DHC) is the most oxidizable lipid molecule reported to date, with a propagation rate constant for free radical peroxidation that is 200 times that of cholesterol. To better understand the high reactivity of 7-DHC and elucidate the reaction mechanism, we synthesized conjugated and skipped nonconjugated cholestadienols that would give one of the two putative pentadienyl-radical intermediates formed in 7-DHC peroxidation. The additional dienols include 6,8(9)-dienol, 5,8(14)-dienol, 6,8(14)-dienol, and the biologically important 8-dehydrocholesterol (8-DHC; 5,8(9)-dienol). We found that all of the dienols are significantly (at least 40 times) more reactive than cholesterol. Among them, dienols leading to the formation of the pentadienyl radical in ring B (termed endo-B) of the sterol are more reactive than those leading to the pentadienyl radical spanning rings B and C (termed exo-B). By comparing the oxysterol profile formed from 7-DHC and those formed from 8-DHC and 5,8(14)-dienol, products formed from abstraction of the hydrogen atoms at C-9 and C-14 (H-9 or H-14 mechanism) were clearly differentiated. When the oxidation was carried out in the presence of the good hydrogen atom donor α-tocopherol, the oxysterol profile of 7-DHC peroxidation differed distinctly from the profile observed in the absence of the antioxidant and resembles more closely the profile observed in biological systems. This study suggests that oxidative stress and the accumulation of oxysterols should be considered as two key factors in cholesterol biosynthesis or metabolism disorders, where dienyl sterol intermediates are accumulated.
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影响因子：
4.2
作者：
de Sain-van der Velden, M. G. M.;Verrips, A.;Visser, G.
通讯作者：
Visser, G.
影响因子：
4.1
作者：
Liu, Wei;Yin, Huiyong;Akazawa, Yoko Ogawa;Yoshida, Yasukazu;Niki, Etsuo;Porter, Ned A.
通讯作者：
Porter, Ned A.
影响因子：
15
作者：
Lamberson CR;Xu L;Muchalski H;Montenegro-Burke JR;Shmanai VV;Bekish AV;McLean JA;Clarke CF;Shchepinov MS;Porter NA
通讯作者：
Porter NA
影响因子：
62.1
作者：
Milne, Ginger L.;Yin, Huiyong;Hardy, Klarissa D.;Davies, Sean S.;Roberts, L. Jackson, II
通讯作者：
Roberts, L. Jackson, II
影响因子：
17.1
作者：
Porter FD;Scherrer DE;Lanier MH;Langmade SJ;Molugu V;Gale SE;Olzeski D;Sidhu R;Dietzen DJ;Fu R;Wassif CA;Yanjanin NM;Marso SP;House J;Vite C;Schaffer JE;Ory DS
通讯作者：
Ory DS