P-GLYCOPROTEIN - A NEW MECHANISM TO CONTROL DRUG-INDUCED NEPHROTOXICITY

The role of P glycoprotein (P-gp) in kidney is now being explored, and under physiological conditions, this protein is thought to be an excr etory pump of cationic xenobiotics and metabolites. Functionally, two different types of P-gp have been described, but only the class I has been related to drug transport, and its overexpression confers the mul tidrug resistance phenotype in tumoral cells. It has been proposed tha t P-gp is involved in the energy-dependent transport of substrates thr ough the cell membrane (toxic metabolites, toxins, nutrients, ions, pe ptides, etc.) - like a 'hydrophobic molecule vacuum cleaner'. Several physiological functions have been attributed to P-gp: defense against xenobiotic aggression and transmembrane transport of prenylcysteine me thyl esters, removing these cytotoxic metabolites from cells. A variet y of substrates ranging from chemotherapeutics to steroid hormones, an tibiotics, and calcium channel blockers can be transported by P-gp, su ggesting the possible involvement of this protein in other unknown fun ctions. Results from our group and others have suggested that overexpr ession of P-gp in renal tubular and mesangial cells prevents pharmacol ogical nephrotoxicity by cyclosporin A (CsA). On the other hand CsA, a substrate of the pump, could act as a blocker in tubular cells by com petitive inhibition. One relevant aspect in kidney is the possible rel ationship between P-gp and protein kinase C. Several reports suggest t hat protein kinase C may play a role in inducing the P-gp overexpressi on in cells under xenobiotic pressure, through activation of the ras o ncoprotein family. This could be mediated directly by angiotensin II a s a ras activator. This way, the detoxicant function of P-gp against p roducts of the ras catabolism could mediate their accumulation when th e 'vacuum cleaner' function is blocked by CsA or tacrolimus, contribut ing to the initial development of fibroblastic activation that leads t o interstitial fibrosis associated with nephrotoxicity by these immuno suppressor drugs. In conclusion, P-gp expression could be an important component of a complex detoxifying system in kidney against xenobioti cs or regulating the traffic of endogenous metabolites responsible for the susceptibility of subjects to the development of nephrotoxicity a gainst different drugs.