Fight Back: Adaptive Responses to Toxicant Exposure

Abstract

The popularity of barbiturate sedatives in bygone days helped physicians discover an unusual property of these medicines: on repeated use, patients experienced a dramatic loss of effectiveness, with higher and higher doses required to elicit the original drug response. This capacity for physical tolerance alerted researchers to the phenomenon of enzyme induction: upon sustained exposure, the liver and other tissues simultaneously boost the expression of enzymes that convert xenobiotics to water-soluble metabolites and membrane transporters that expel metabolites via bile or urine. These outcomes reflect the actions of xenosensors – bifunctional proteins that detect ingested xenobiotics and then activate broad transcriptional responses that facilitate their clearance from the body. While such adaptive changes protect the body by altering the toxicokinetic fate of xenobiotics, transcriptional changes also occur at the subcellular level to protect tissues against cell-damaging reactive metabolites. Upon detecting cell or protein damage caused by electrophiles, cells mount strong transcriptional responses to suppress the toxicodynamic properties of xenobiotics via a number of pathways including the heat shock response, the antioxidant response, the unfolded protein response and the NFkB pathway.