Regulation of drug metabolism and transporters

Drug metabolizing enzymes (DME) play a central role in the intestinal absorption/permeability, metabolism, elimination and detoxification of endogenous and exogenous compounds. DME include phase I and II metabolizing enzymes. The hydroxylation activity of phase I DME increases the hydrophilicity of the molecules. The electrophilicity of phase I DME-derived products is reduced via conjugation with endogenous ligands, such as glutathione and glucuronic acid, and facilitates their inactivation and excretion in the bile and/or the urine. The transport system is involved in the cellular input/output of molecules and drugs. Numerous endogenous and exogenous compounds, being the substrates of DME, regulate the expression of DME genes through the activation of a number of nuclear receptors. These nuclear receptors directly or indirectly target different regulatory sequences present in the promoter region of the DME genes. The review describes the activation process of nuclear receptors, as well as their interactions to elucidate the extended cross-talk between them in the regulation of DME.