The Challenges of Dealing with Promiscuous Drug-Metabolizing Enzymes, Receptors and Transporters

Unlike classical enzymes, drug-metabolizing enzymes (DMEs), such as the liver microsomal cytochrome P450, UDP-glucuronyltransferase, epoxide hydrolase, and flavin-containing monooxygenase, all exhibit broad substrate specificities, low turnover rates, atypical kinetics, and other unusual properties. Receptors (the pregnane X receptor, NR1I2; the constitutive androstane receptor, NR1I3; and the aromatic hydrocarbon receptor) responsible for the induction of DMEs and transporters (P-glycoprotein) responsible for drug transport also have broad substrate specificities. These promiscuous proteins are all intimately involved in drug disposition. Promiscuous proteins, by definition, are known for diversity, but not specificity, in their interaction with drugs. In this review, we analyzed recent advances on the three dimensional structures and kinetic properties of DMD proteins from crystallography, mutational, and kinetic studies to gain insights into the structural and biochemical basis for the promiscuous ligand-protein interactions of the proteins. Large substrate-binding cavities (SBCs), binding of more than one substrate/effector and binding of substrates in alternative orientations and locations within the SBCs, rotation of a substrate at the active site, and substantial substrate-induced conformational changes of the SBCs are common features of the promiscuous DMEs, receptors, and transporters, and therefore, are important parameters to be considered in dealing with drug metabolism issues and safety evaluation of drugs and environmental chemicals.