Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation

Cytochrome P450 (CYP) enzymes catalyse the oxidative conversion of drugs and other lipophilic compounds to hydrophilic metabolites. Thus, CYPs play a dominant role in the elimination of drugs from the body. Inhibitory interactions occur when drugs compete for oxidation by specific CYPs whereas certain drugs increase the capacity for oxidative biotransformation by inducing the synthesis of new CYPs. Methylenedioxyphenyl (MDP) compounds have been widely employed as commercially important pesticide synergists and a number of derivatives are found in oils and spices. MDP compounds are of considerable toxicological significance because of their capacity to inhibit and induce CYP enzymes in mammals; some derivatives produce neurotoxic and hepatotoxic effects. Although there are relatively few therapeutic agents of present clinical importance that possess the MDP structural feature, the synthesis and preclinical evaluation of such agents appears to be increasing. In the context of the existing literature surrounding MDP compounds it is noteworthy that these potential drugs also elicit significant modulatory effects on CYP activities in rat and human liver. These developments indicate the importance of understanding the chemical mechanisms by which MDPs interact with CYPs. Thus, the presence of the MDP structure may undermine the potential clinical value of new drugs.