Ronnenberg W C, Wang Y, Baker M T
Department of Anesthesia, University of Iowa, Iowa City 52242, USA.
Biochem Pharmacol. 1995 Aug 8;50(4):521-8. doi: 10.1016/0006-2952(95)00161-r.
Isoflurane stimulates the metabolism of 2-chloro-1,1-difluoroethene (CDE) in liver microsomes from phenobarbital-treated rats or rabbits. The P450 isozymes involved and the mechanism by which such stimulation occurs have not been clarified. The present study examined the effects of isoflurane and cytochrome b5 on CDE metabolism in reconstituted systems containing purified rat CYP2B1 or CYP2C6. Under similar incubation conditions, CYP2B1 defluorinated CDE at approximately five times the rate of CYP2C6. Isoflurane was a potent stimulator of CDE metabolism, increasing it nearly 5-fold when catalyzed by CYP2B1, but only 2-fold when catalyzed by CYP2C6. Isoflurane had no stimulatory effect on benzphetamine metabolism by CYP2B1 or CYP2C6. Cytochrome b5 was not required for isoflurane-facilitated CDE metabolism; however, the addition of cytochrome b5 to CYP2B1 increased CDE metabolism 71 and 44%, in the absence and presence of isoflurane, respectively. In reconstituted CYP2B1, isoflurane generated a type I difference spectrum of approximately twice the magnitude of CDE and stimulated NADPH consumption more so than CDE. The same quantity of NADPH was consumed when CDE was present with isoflurane as compared with isoflurane alone. These data support the hypothesis that isoflurane stimulates CDE metabolism by a mechanism involving increased P450 reduction via direct isoflurane interaction with P450.
异氟烷可刺激经苯巴比妥处理的大鼠或兔肝脏微粒体中2-氯-1,1-二氟乙烯（CDE）的代谢。所涉及的细胞色素P450同工酶以及这种刺激发生的机制尚未阐明。本研究检测了异氟烷和细胞色素b5对含有纯化大鼠CYP2B1或CYP2C6的重组系统中CDE代谢的影响。在相似的孵育条件下，CYP2B1使CDE脱氟的速率约为CYP2C6的5倍。异氟烷是CDE代谢的强效刺激剂，由CYP2B1催化时可使其增加近5倍，而由CYP2C6催化时仅增加2倍。异氟烷对CYP2B1或CYP2C6催化的苄非他明代谢无刺激作用。异氟烷促进的CDE代谢不需要细胞色素b5；然而，在不存在和存在异氟烷的情况下，向CYP2B1中添加细胞色素b5分别使CDE代谢增加71%和44%。在重组的CYP2B1中，异氟烷产生的I型差光谱约为CDE的两倍，并且比CDE更能刺激NADPH的消耗。与单独使用异氟烷相比，当CDE与异氟烷同时存在时消耗的NADPH量相同。这些数据支持以下假设，即异氟烷通过涉及异氟烷与细胞色素P450直接相互作用增加细胞色素P450还原的机制来刺激CDE代谢。
