P-GLYCOPROTEIN FUNCTIONS AND SUBSTRATES - POSSIBLE ROLES OF MDR1 GENEIN THE KIDNEY

There is a renewed attention on the multidrug resistance genes and the ir products, P-glycoproteins, since recent molecular and functional st udies revealed unexpected functions in normal tissues. There are two t ypes of human P-glycoprotein: Type I, encoded by the MDR1 gene, presen t in excretory organs and in non-polarized cells; and Type II, encoded by MDR2, present in the canalicular membrane of hepatocytes. MDR1 Pgp transports xenobiotics, peptides, steroids, and phospholipids, and is also a regulator of swelling-activated chloride channels. MDR2 Pgp is exclusively a phosphatidylcholine translocase. In the kidney, the MDR 1 gene and protein are expressed in mesangial, proximal tubule, thick loop of Henle, and collecting duct cells. In mesangial and proximal tu bule cells Pgp transports xenobiotics. Concomitant exposure of kidney cells to two Pgp substrates results in increased cell toxicity. Extrac ts from supernatants of mesangial cell cultures inhibit Pgp-mediated t ransport, suggesting that a mesangial-cell metabolite could be a subst rate of Pgp. Active vitamin D-3 and platelet activating factor inhibit Pgp transport and are possible endogenous substrates in proximal tubu le and mesangial cells, respectively. Pgp could be also a regulator of swelling-activated chloride channels present in the kidney.