Role of the glutathione pathway and ABC-transporter family in drug elimination and defense from ROS-mediated oxidative stress. Shaded diamonds represent intracellular drug and drug metabolites. Glutathione (GSH) is represented by clear pentagons. The rate-limiting step in its de novo biosynthesis is the enzyme glutamate-cysteine ligase (GCL). The balance of drug/drug metabolites and intracellular GSH is a significant determinant of drug levels and ROS stress. Glutathione peroxidase 1 (GPx1) reduces hydrogen peroxide generated after exposure to certain drugs, by oxidizing GSH to its disulfide form GSSG. Glutathione S-transferases (GST) conjugate GSH to drugs and drug metabolites, thus facilitating drug-conjugate elimination and efflux. GSTs also function as peroxidases to a lesser extent than GPx1 (not shown for simplicity). The ABC transporters ABCB1 (MDR1), ABCC1 (MRP1), and ABCC2 (MRP2) among others are involved in ATP-dependent efflux of drugs or drug-GS conjugates.