Induction of cytochrome P-450 isozymes during long-term nifedipine administration

Abstract

The wide substrate specificity of the microsomal monooxygenase system, catalyzing oxidation of many xenobiotics and endogenous compounds, is determined by the existence of multiple forms of cytochrome P-450 [13]. A modern approach to the characterization and identification of the individual cytochrome P-450 isozymes is to study specific reactions catalyzed by these hemoproteins. There are substrates whose metabolism is more specific for a particular cytochrome P-450 isozyme. For example, the O-de-ethylation of 7-ethoxyresorufin is catalyzed by cytochrome P-450 c [3] . The steroid hormones testosterone, androstenedione (AD), and progesterone are utilized as specific substrates by the microsomal monooxygenase of the liver, with well-marked regional and stereospecificity of metabolism [16]. The rate of formation of hydroxylated metabolites gives information on activity of different forms of cytochrome P-450. For example, the formation of 16a-OH-AD is catalyzed by cytochrome P-450h, which is characterized only of male rats. The formation of 16~-OH-AD is catalyzed by P-45%, that of 7a-OH-AD by cytochrome P-450a, and that of 6fl-OH-AD by cytochrome P-450p [15]. Thus the specificity of the reaction of metabolism of certain substrates can serve as an important criterion for the identification of many forms of cytochrome P-450. On the other hand, the immunochemical method using monospecific antibodies against individual cytochrome P-450 isozymes makes it quantitative and qualitative determination in microsomes possible. This combined approach can be used in pharmacologic investigations, especially those in which the drug influences the microsomal monooxygenase system. The calcium antagonist nifedipine, widely used in cardiologic practice, is metabolized by cytochrome P-450p in rat liver microsomes [6] or by P-450NF in human liver microsomes [14], which are induced by the synthetic steroid pregnenolone-16carbonitrile and steroids of the glucocorticoid class, such as dexamethasone and macrolide antibiotics [12]. Previously the writers described induction of a cytochrome P-450-dependent monooxygenase system after long-term administration of nifedipine to rats [7]. The aim of the present investigation was to discover what forms of cytochrome P-450 can be induced under these conditions.