Selective inactivation of cytochrome P-450 isozymes by suicide substrates.
Selective inactivation of cytochrome P-450 isozymes by suicide substrates.
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自杀底物选择性失活细胞色素 P-450 同工酶。
DOI：
10.1016/0003-9861(81)90239-3
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发表时间：
1981
影响因子：
3.9
通讯作者：
Lu,AY
中科院分区：
文献类型：
--
作者：
OrtizdeMontellano,PR;Mico,BA;Mathews,JM;Kunze,KL;Miwa,GT;Lu,AY
本文研究了以下六种底物在体外对细胞色素P-450的自催化破坏作用：2-异丙基-4-戊烯胺、1-乙基环戊醇、17-α-丙二烯-19-去甲睾酮、荧烯、5，6-二氯-1，2，3-苯并噻二唑和1-氨基苯并三氮唑。用前三种底物处理苯巴比妥(Pb)或3-甲基胆蒽(3-MC)处理的大鼠，或将它们与这类大鼠的肝微粒体孵育，可使铅处理的大鼠膜细胞色素P-450水平比3-MC处理的大鼠下降得更大。然而，当使用最后三种药物时，同时使用铅和3-MC的大鼠的微粒体中也观察到了类似的损失。用从铅或3-MC处理的大鼠肝微粒体中纯化的主要细胞色素P-450同工酶也进行了类似的实验。在六种底物的催化周转过程中，铅同工酶都失活，而只有三种底物(DCBT、ABT和荧烯)使3-MC同工酶失活。用纯化的酶进行的耗氧量研究表明，AIA不是3-MC同工酶的可测量底物，这一事实解释了它未能灭活该同工酶的原因。与铅同工酶类似的研究表明，大约每230-320个AIA分子被该酶处理后，就有一个酶分子失活。
The autocatalytic destruction of cytochromeP-450 by the following six substrates has been investigatedin vivoandin vitrowith microsomal and purified, reconstituted rat liver enzymes: 2-isopropyl-4-pentenamide (AIA), 1-ethinylcyclopentanol, 17α-propadienyl-19-nortestosterone, fluroxene, 5,6-dichloro-1,2,3-benzothiadiazole (DCBT), and 1-aminobenzotriazole (ABT). Administration of the first three substrates to rats pretreated with either phenobarbital (Pb) or 3-methylcholanthrene (3-MC), or their incubation with hepatic microsomes from such rats, produced a larger decrease in cytochromeP-450 levels in the membranes from Pb- than 3-MC-treated rats. Comparable losses, however, were observed in microsomes from rats pretreated with both Pb and 3-MC when the last three agents were used. Similar experiments were carried out using the major cytochromeP-450 isozymes purified from liver microsomes of Pb- or 3-MC-treated rats. The Pb isozyme was inactivated during catalytic turnover of all six substrates while only three substrates (DCBT, ABT, and fluroxene) were found to inactivate the 3-MC isozyme. Oxygen consumption studies with purified enzymes have shown that AIA is not a measurable substrate for the 3-MC isozyme, a fact which explains its failure to inactivate this isozyme. Similar studies with the Pb isozyme establish that one enzyme molecule is inactivated for approximately every 230–320 AIA molecules processed by the enzyme.