Nuclear Receptors: the Controlling Force in Drug Metabolism of the Liver?

The body is in a constant battle to achieve homeostasis; indeed, the robustness with which it can respond to moves away from homeostasis is a vital part in the survival of the organism as a whole. There thus exists a need for a network of sensors that are able to capture, interpret, and respond to alterations in chemical levels that move the body away from homeostasis and this applies to both endogenous and exogenous chemicals. With respect to external chemicals (xenobiotics), this xenosensing is often carried out through specific interactions with cellular receptors. The phenomenon of 'xenosensing' has attracted much interest of late, whereby xenobiotics interact with receptors resulting in the activation of a battery of genes mediating oxidative drug metabolism, conjugation, and transport, thereby enhancing the elimination of the xenobiotic by the organism. However, this beneficial response is counterbalanced by the increasingly recognized role of nuclear receptors in mediating drug-drug interactions via enzyme induction or the production of toxicity through interaction with endogenous pathways. This review will focus on the role of nuclear receptors in mediating these effects, and how such knowledge will contribute to a mechanism-based risk assessment for xenobiotics.