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

Abstract

An experimental method is described to deplete markedly in vivo the cytochrome P-450 content of rat liver for prolonged periods of time. The method uses the synthetic metalloporphyrin Co heme (Co 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 Co-heme (125 .mu.mol/kg of body wt) decreased within 48 h hepatic cytochrome P-450 to .apprxeq. 20% of normal, at which level it remained for 10 days; normal levels were not achieved by 36 days. Periodic administration (total, 6 injections) of a smaller dose of Co-heme (50 .mu.mol/kg of body wt) maintained the cytochrome p-450 content at levels .apprxeq. 15% of normal for > 90 days with concurrent profound impairment of mono-oxygenase reactions catalyzed by this heme protein. The ability of Co-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.