The cytochrome P-450-depleted animal: an experimental model for in vivo studies in chemical biology.

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.