Inactivation of multiple hepatic cytochrome P-450 isozymes in rats by allylisopropylacetamide: mechanistic implications

LM Bornheim, MC Underwood, P Caldera, AE Rettie, WF Trager, SA Wrighton and MA Correia

In vivo administration of the porphyrogenic agent allylisopropylacetamide (AIA) to phenobarbital-pretreated rats results in marked loss of hepatic cytochrome P-450 content. Using isozyme- selective functional markers, we now show that such loss reflects inactivation of several phenobarbital-inducible and constitutive isozymes. Some of the isozymes (P-450a,b,h and PB-1) are largely reparable by reconstitution with exogenous hemin, indicating that after AIA-mediated loss of their prosthetic heme, their apoprotein moieties are essentially intact and functionally reconstitutable with hemin. On the other hand, after AIA-mediated inactivation, isozymes such as cytochrome P-450p remain refractory to such repair. The cause for such intractability remains somewhat elusive since AIA-mediated alkylation of the apocytochrome, proteolytic loss of the hemoprotein, or even irreversible binding of prosthetic heme catabolites to the apocytochrome does not appear to be responsible.

Volume 32, Issue 1, pp. 299-308, 08/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics

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