Burke M D, Mayer R T
Chem Biol Interact. 1983 Jul 15;45(2):243-58. doi: 10.1016/0009-2797(83)90072-8.
The metabolism and cytochrome P-450-binding of phenoxazone and a homologous series of its n-alkyl ethers (1-8C) was studied in hepatic microsomes of control, phenobarbitone-pretreated (PB) and 3-methylcholanthrene-pretreated (3MC) C57/BL10 mice. Phenoxazone and its ethers were hydroxylated and O-dealkylated respectively to a common metabolite, resorufin. The three categories of microsomes differed greatly in activity for the metabolism and binding of the various substrate homologues. The most rapidly metabolised substrates for control microsomes were phenoxazone and its shortest-chain ethers, for PB microsomes phenoxazone and the pentyl ether, and for 3MC microsomes the ethyl and propyl ethers. The variations in activity occurred in Vmax rather than in the apparent Km-value. All the ethers gave Type I cytochrome P-450-binding spectra. The substrates giving the largest Type I spectra were the same for all microsomes--the ethyl, propyl and butyl ethers--but the magnitudes of the spectra differed in the order 3MC- greater than PB- greater than control microsomes. Phenoxazone and resorufin gave Modified Type II cytochrome P-450-binding spectra. PB-induction was most marked for the depentylation reaction (increased 101-fold), whereas 3MC-induction was most marked for depropylation and debutylation (88- and 96-fold). The intermicrosomal differences were interpreted as reflecting the different metabolic specificities of variant forms of cytochrome P-450. Substrate lipophilicity increased with increasing ether chain length and was not a major influence on specificity. The main substrate influence on specificity was steric, due to the presence and length of the ether side chain. The preeminent effect of ether chain length was considered to be on the rate of substrate transformation rather than on substrate interaction with cytochrome P-450.
在对照、苯巴比妥预处理（PB）和3-甲基胆蒽预处理（3MC）的C57/BL10小鼠的肝微粒体中，研究了吩恶嗪及其一系列正烷基醚（碳链长度为1 - 8个碳）的代谢和细胞色素P - 450结合情况。吩恶嗪及其醚分别被羟基化和O - 脱烷基化生成共同的代谢产物试卤灵。这三类微粒体在各种底物同系物的代谢和结合活性上有很大差异。对照微粒体中代谢最快的底物是吩恶嗪及其最短链醚，PB微粒体中是吩恶嗪和戊基醚，3MC微粒体中是乙基和丙基醚。活性变化发生在最大反应速度（Vmax）而非表观米氏常数（Km值）上。所有醚都给出I型细胞色素P - 450结合光谱。所有微粒体中产生最大I型光谱的底物相同——乙基、丙基和丁基醚——但光谱强度顺序为3MC微粒体＞PB微粒体＞对照微粒体。吩恶嗪和试卤灵给出改良II型细胞色素P - 450结合光谱。PB诱导对脱戊基反应最为显著（增加101倍），而3MC诱导对脱丙基和脱丁基反应最为显著（分别增加88倍和96倍）。微粒体间的差异被解释为反映了细胞色素P - 450变体形式的不同代谢特异性。底物亲脂性随醚链长度增加而增加，且不是特异性的主要影响因素。底物对特异性的主要影响是空间位阻，这是由于醚侧链的存在和长度所致。醚链长度的主要影响被认为是对底物转化速率而非底物与细胞色素P - 450的相互作用。
