Harnessing P-glycoprotein induction and activation: A protective strategy against xenobiotic-induced toxicity

: Membrane transporters, expressed across major organs, are essential for evaluating the pharmacokinetics of xenobiotics. Among them, P-glycoprotein (P-gp/MDR1/ABCB1), a major apical efflux transporter of the ATP-binding cassette (ABC) superfamily, plays a central protective role at the intestine, liver, kidney, and blood–brain barrier (BBB) by limiting the intracellular accumulation of xenobiotics and facilitating their excretion. While P-gp inhibition has been widely studied for overcoming multidrug resistance in cancer, emerging evidence suggests that positive modulation of P-gp— either through transcriptional induction (a delayed, nuclear-receptor-mediated increase in P-gp expression) or through direct activation (a rapid, post-translational enhancement of the intrinsic efflux activity of membrane-bound P-gp)—may enhance detoxification and mitigate drug-induced toxicity. In enterocytes, hepatocytes, proximal tubular epithelial cells, and brain endothelial cells, compounds that increase P-gp expression (inducers) or activity (activators) reduce substrate bioavailability, systemic exposure, or CNS penetration, thereby offering therapeutic opportunities for toxicity management. This review synthesizes current knowledge on compound-mediated positive P-gp modulation, highlighting experimental evidence of its capacity to reduce xenobiotic-induced toxicity. Collectively, these insights position P-gp as a promising pharmacological target for enhancing drug safety and fostering more effective and individualized therapies. Harnessing P-gp modulation thus offers a promising avenue for safer therapeutic strategies across diverse organ systems. Importantly, the available evidence supporting positive P-gp modulation as a detoxification strategy currently derives from preclinical in vitro and in vivo studies; future research should focus on its translation into human pharmacotherapy.