Drummond G S, Kappas A
Proc Natl Acad Sci U S A. 1982 Apr;79(7):2384-8. doi: 10.1073/pnas.79.7.2384.
An experimental method is described to deplete markedly in vivo the cytochrome P-450 content of liver for prolonged periods of time. The method uses the synthetic metalloporphyrin cobalt-heme (cobalt protoporphyrin IX), which possesses the dual biological properties of repressing delta-aminolevulinate synthase, the rate-limiting enzyme of heme biosynthesis, and of potently inducing microsomal heme oxygenase, the rate-limiting enzyme of heme catabolism. A single dose of cobalt-heme (125 mumol/kg of body weight) decreased within 48 hr hepatic cytochrome P-450 to approximately 20% of normal, at which level it remained for 10 days; normal levels were not achieved by 36 days. Periodic administration (total, six injections) of a smaller dose of cobalt-heme (50 mumol/kg of body weight) maintained the cytochrome P-450 content at levels approximately 15% of normal for greater than 90 days with concurrent profound impairment of mono-oxygenase reactions catalyzed by this heme protein. The ability of cobalt-heme to produce profound and prolonged depletion of cytochrome P-450 in vivo provides a valuable model for examining the role of cytochrome P-450-dependent metabolism in the biology of endogenous and exogenous chemicals.
本文描述了一种实验方法，可在体内长时间显著降低肝脏细胞色素P-450的含量。该方法使用合成金属卟啉钴血红素（钴原卟啉IX），它具有双重生物学特性，既能抑制血红素生物合成的限速酶δ-氨基乙酰丙酸合酶，又能强力诱导血红素分解代谢的限速酶微粒体血红素加氧酶。单次给予钴血红素（125 μmol/kg体重）可在48小时内使肝细胞色素P-450降至正常水平的约20%，并在该水平维持10天；36天内未恢复到正常水平。定期给予较小剂量的钴血红素（50 μmol/kg体重，共注射六次）可使细胞色素P-450含量维持在正常水平的约15%达90多天，同时该血红素蛋白催化的单加氧酶反应受到严重损害。钴血红素在体内产生深度且持久的细胞色素P-450耗竭的能力，为研究细胞色素P-450依赖性代谢在内源性和外源性化学物质生物学中的作用提供了一个有价值的模型。
