Marcus D L, Halbrecht J L, Bourque A L, Lew G, Nadel H, Freedman M L
Biochem Pharmacol. 1984 Jul 1;33(13):2005-8. doi: 10.1016/0006-2952(84)90565-3.
Cimetidine is a well known inhibitor of the heme-containing enzyme cytochrome P-450. We have found that it also inhibits delta-aminolevulinic acid synthase (ALA-S) and microsomal heme oxygenase, the rate-limiting enzymes for heme synthesis and heme degradation respectively. Cytochrome P-450 content was decreased but microsomal heme concentration remained unaltered for a period of 30 min after in vivo cimetidine administration to rats. In vitro incubation of cimetidine with each of the above enzymes revealed no direct effect of cimetidine on ALA-S but about 50% inhibition of heme oxygenase and 20% reduction in cytochrome P-450 content. This suggests that a metabolite of cimetidine inhibits ALA-S activity in vivo, while the drug itself or a metabolite inhibits heme oxygenase both in vivo and in vitro. A rise in ALA-S activity seen after its early inhibition and its return to approximate control values after 60 min suggest a reversible inhibition of ALA-S by a metabolite of cimetidine and may correspond to its clearance from the animal. An elevation in microsomal heme content paralleled the rise in ALA-S activity while microsomal heme oxygenase activity returned to only 65% of control value 60 min after cimetidine treatment. Cytochrome P-450 content did not change after its initial decrease, suggesting that irreversible alteration had occurred.
西咪替丁是一种著名的含血红素酶细胞色素P - 450的抑制剂。我们发现它还能抑制δ-氨基乙酰丙酸合酶（ALA - S）和微粒体血红素加氧酶，这两种酶分别是血红素合成和血红素降解的限速酶。给大鼠体内注射西咪替丁30分钟后，细胞色素P - 450含量降低，但微粒体血红素浓度保持不变。西咪替丁与上述每种酶的体外孵育显示，西咪替丁对ALA - S没有直接作用，但对血红素加氧酶有大约50%的抑制作用，细胞色素P - 450含量降低20%。这表明西咪替丁的一种代谢产物在体内抑制ALA - S活性，而药物本身或一种代谢产物在体内和体外均抑制血红素加氧酶。早期抑制后观察到的ALA - S活性升高以及60分钟后恢复到近似对照值，提示西咪替丁的一种代谢产物对ALA - S有可逆性抑制作用，这可能与其从动物体内清除有关。微粒体血红素含量的升高与ALA - S活性的升高平行，而微粒体血红素加氧酶活性在西咪替丁治疗60分钟后仅恢复到对照值的65%。细胞色素P - 450含量在最初降低后没有变化，提示发生了不可逆改变。
