Heme enhances hexobarbital metabolism in perfused rat liver after drug-mediated destruction of cytochrome P-450.

During mixed-function oxidation of allylisopropylacetamide (AIA), autocatalytic destruction of hepatic cytochrome P-450 leads to retarded elimination of this agent. After AIA-mediated destruction of cytochrome P-450, exogenously administered heme that has entered liver cells is directly incorporated into cytochrome P-450. This raises the hepatic content of this hemoprotein, enhances the activity of mixed-function oxidases and accelerates hepatic clearance of the inactivating agent, AIA. We have studied the metabolic consequences of these phenomena for the disposition of hexobarbital coadministered with AIA in the isolated perfused rat liver. AIA decreased perfusate fractional disappearance of hexobarbital by approximately 80%. This was attributable to destruction of cytochrome P-450 rather than to competitive inhibition of hexobarbital metabolism, since by increasing the molar ratio of hexobarbital to AIA in perfusate, hexobarbital elimination was not enhanced. Heme administered after AIA significantly accelerated hexobarbital disappearance from the perfusate, reflecting increased hexobarbital metabolism by reconstituted cytochrome P-450. In the absence of prior destruction of cytochrome P-450 by AIA, heme failed to alter the rate of hexobarbital elimination. These findings demonstrate that drug-mediated destruction of cytochrome P-450 results in impaired hexobarbital metabolism, which is reversible by administration of heme. Heme infusion may be useful in treatment of patients poisoned with drugs that destroy hepatic cytochrome P-450.