Significance of Posttranslational Modification of Drug Metabolizing Enzymes by Phosphorylation for the Control of Carcinogenic Metabolites

Abstract

The total activity of foreign compound metabolizing enzymes may change by altering the amount or the specific activity of the enzyme by induction or repression, or by activation or inhibition. The important contribution of enzyme induction is well known (Conney 1982, Oesch 1986, Nebert and Jones 1989). This is a relatively slow process which requires the biosynthesis of the enzyme protein. The possibility of a faster regulation of foreign compound metabolism by posttranslational modification by phosphorylation of an already preexisting protein molecule has only recently received attention. A central role in the metabolism of foreign compounds is played by the cytochrome P450-dependent monooxygenase. A few studies on phosphorylation of components of the cytochrome P450 dependent monooxygenases are available (Pyerin et al. 1983, Pyerin et al. 1987, Jansson et al. 1987, Epstein et al. 1989, Koch and Waxman 1989, Eliasson et al. 1990, Bartlomowicz et al. 1989a, 1989b, Oesch-Bartlomowicz et al. 1990), most of them in cell-free systems. The purpose of this chapter is to summarize the present information on the occurrence of phosphorylation of cytochromes P450 in intact cells, on its regulation by extracellular hormones and intracellular second messengers and on its impact in isoenzyme-selective metabolism of foreign compounds and on their genotoxic effects.