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Abstract
1. Aphidicolin is shown to undergo rapid metabolism by rat-liver microsomes resulting in its inactivation and loss of its DNA polymerase α/δ inhibition. Metabolism of aphidicolin was not observed with cytosolic enzymes of rat liver and was inconsistent with the involvement of microsomal 3δ-hydroxysteroid oxidoreductases.
2. Rates of aphidicolin inactivation as a function of microsomal enzyme induction (pernmol cytochrome P-450) followed the order: untreated microsomes > dexamethasone-induced > phenobarbital-induced > β-naphthoflavone-induced > clofibrate-induced.
3. The principal metabolic process, constituting >90% of the metabolic profile, produces 3-ketoaphidicolin 2, which exhibits ~10% of the activity of aphidicolin in inhibition of DNA polymerase α. This metabolic transformation, the oxidation of an alcohol to a ketone, is an unusual, but not unique conversion, for cytochrome P-450.
4. 3-Ketoaphidicolin 2 is an intermediate and ultimately undergoes 18-dehydroxymethylation to produce 18-noraphidicolinones 3, which are inactive in the inhibition of DNA polymerase α.
5. A specific constitutive cytochrome P-450 isozyme, involved in endogenous steroid regulation, was implicated as the species responsible for aphidicolin metabolism in vitro.