Modulatory effects of hormones, drugs, and toxic events on renal organic anion transport.
The human body is exposed continuously to a wide variety of exogenous compounds, many of which are anionic compounds. In addition, products of phase II biotransformation reactions are negatively charged, viz. glucuronides, sulfate esters, or glutathiones. Renal transport of organic anions is an important defense mechanism of the organism against foreign substances. The combination of the rate of uptake and efflux and the intracellular disposition of organic anions in the proximal tubule determines the intracellular concentration and the nephrotoxic potential of a compound. Modulation of organic anion secretion is observed after exposure of proximal tubules to various hormones, and the subsequent receptor-mediated response is signaled by protein kinases. Transport of anionic compounds across the basolateral as well as the luminal membrane is modified by activation or inhibition of protein kinases. Protein kinase C activation reduces the uptake of organic anions mediated by the organic anion transporter 1 (OAT1/Oat1) and Oat3 and reduces Mrp2-mediated efflux. In addition, activation of protein kinase C has been shown to inhibit transport by the organic anion transporting polypeptide 1 (Oatp1) across the luminal membrane. Additional protein kinases have been implicated in the regulation of organic anion transport, and the role of nuclear factors in xenobiotic excretion is an emerging field. The physiological regulation of organic anion transporters may also be influenced by exogenous factors, such as exposure to xenobiotics and cellular stress. This commentary discusses the current knowledge of endogenous and exogenous influences on renal anionic xenobiotic excretion.
Department of Pharmacology and Toxicology 233, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
Sylvie A
SA
Terlouw
Rosalinde
R
Masereeuw
Frans G M
FG
Russel
D000838:Anions / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D006728:Hormones / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D011494:Protein Kinases / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015262:Xenobiotics / Q000494:pharmacology*
D000838:Anions; D006728:Hormones; D027361:Organic Anion Transporters; D015262:Xenobiotics; D011494:Protein Kinases