Selective inhibitors of cytochromes P450.

The balance between detoxification and bioactivation of a compound in a particular species or organ is highly dependent on the relative amounts and activities of the different forms of cytochrome P450 (P450) that are expressed. Therefore, knowledge of the catalytic specificities and regulation of individual P450 forms is of paramount importance in predicting and/or rationalizing species, strain, and individual differences in xenobiotic metabolism as well as metabolic interactions between compounds, both endogenous and exogenous. The emergence in recent years of a battery of isoform-selective chemical inhibitors that can be used in vitro and in vivo in experimental animals and humans has greatly facilitated the identification of individual cytochromes P450 responsible for specific bioactivation and detoxification reactions. Many of these inhibitors are mechanism-based and owe their selectivity to metabolism by the target enzyme. Such compounds have also proven valuable as probes of the catalytic mechanism of cytochromes P450, for identifying amino acid residues of importance for the various functions of the enzyme, for assessing the physiological roles of P450-derived oxidation products of endogenous compounds, in chemical-induced models of acute hepatic porphyria, and for studying protein turnover. The identification of isoform-selective, nontoxic inhibitors of individual human cytochromes P450 raises the real possibility of modulation of human drug metabolism for therapeutic purposes.