Jensen J C, Gugler R
Biochem Pharmacol. 1985 Jun 15;34(12):2141-6. doi: 10.1016/0006-2952(85)90408-3.
The O-deethylation of 7-ethoxycoumarin was inhibited in a mixed type manner by cimetidine in vitro and in microsomes isolated from rats treated with cimetidine in vivo. It was found that the inhibition was even greater if cimetidine was preincubated with the microsomal suspension in the presence of an NADPH-generating system prior to the addition of substrate. In vitro the decrease in activity was accompanied by a decrease in cytochrome P-450 content. This decrease was unaffected by the addition of EDTA to the microsomal suspensions, eliminating the possibility that free radical production was responsible for the decrease in cytochrome P-450. The decrease in activity and cytochrome P-450 content following preincubation of microsomal suspensions with cimetidine could be attenuated if potassium ferricyanide was added to the suspensions. The deethylation activity and cytochrome P-450 content of liver microsomes prepared from cimetidine-treated rats was decreased compared to control animals. The activity and cytochrome P-450 content of microsomes from cimetidine-treated rats could also be restored if microsomes were washed with potassium ferricyanide prior to incubation with substrate. It is proposed that an intermediate complex of cimetidine and cytochrome P-450 could be involved in the inhibition of microsomal metabolism by cimetidine.
西咪替丁在体外以及在从体内经西咪替丁处理的大鼠分离出的微粒体中，以混合型方式抑制7-乙氧基香豆素的O-去乙基化反应。研究发现，如果在添加底物之前，先将西咪替丁与微粒体悬浮液在存在NADPH生成系统的情况下预孵育，抑制作用会更强。在体外，活性降低伴随着细胞色素P-450含量的减少。向微粒体悬浮液中添加EDTA并不会影响这种减少，排除了自由基产生导致细胞色素P-450减少的可能性。如果向悬浮液中添加铁氰化钾，微粒体悬浮液与西咪替丁预孵育后活性和细胞色素P-450含量的减少会减弱。与对照动物相比，从经西咪替丁处理的大鼠制备的肝微粒体的去乙基化活性和细胞色素P-450含量降低。如果在与底物孵育之前用铁氰化钾洗涤微粒体，经西咪替丁处理的大鼠微粒体的活性和细胞色素P-450含量也可以恢复。有人提出，西咪替丁与细胞色素P-450的中间复合物可能参与了西咪替丁对微粒体代谢的抑制作用。
