Regulation of renal tubular secretion of organic compounds

Abstract

Despite considerable advances in the understanding of basic transport pathways and mechanisms involved in the tubular secretion of organic compounds, there is still relatively little information on the regulation of this transport. Studies combining the techniques of integrative and cell physiology and molecular biology will provide significant new insights into the pathways regulating the tubular transport of these compounds.

Estimating pesticide dose from urinary pesticide concentration data by creatinine correction in the Third National Health and Nutrition Examination Survey (NHANES-III)

“…It should be noted that the tubular secretion processes are not strictly linear because an increase of a tubularly-secreted pesticide analyte in the blood may not always lead to an increased elimination. Each facilitated renal transport system has a maximal rate, or transport maximum (Tm), at which it can secrete a given solute with a molecular size too large to allow passage through the glomerular filter (Berkhin and Humphreys, 2001). In this process, a specific carrier protein can bind to one of possibly several ligands, such as a pesticide analyte.…”

Individual PKC-Phosphorylation Sites in Organic Cation Transporter 1 Determine Substrate Selectivity and Transport Regulation

“…Regulation of these transporters has great physiological and even clinical significance for the secretion of multiple endogenous metabolites, drugs, and xenobiotics. Stimulation of this process can accelerate detoxification, whereas inhibition can prolong the exposition of the body to dangerous substances (13).…”

The Molecular Pharmacology of Organic Anion Transporters: from DNA to FDA?

“…The second of the large loops is intracellular and has several canonical protein kinase C (PKC) phosphorylation sites (Sweet et al, 2001;You, 2002). However, although PKC is known to suppress OAT-mediated transport (reviewed in Berkhin and Humphreys, 2001;You, 2002;Terlouw et al, 2003), these canonical PKC sites do not seem to be involved in this process: PKC down-regulation of OAT1 function was not accompanied by OAT1 phosphorylation (You et al, 2000), and, more definitively, down-regulation was unaffected by mutation of the PKC sites (Wolff et al, 2003). It is interesting that the OATs (like other MFS proteins) manifest subtle, but significant, sequence homology (and thus presumed structural similarity) between their Nand C-terminal halves [trans-membrane domains (TMD) 1-6 and 7-12] (Saier et al, 1999;Burckhardt and Wolff, 2000).…”

“…Although this pathway has been studied as a physiological process for more than a century, only within the last several years, with the cloning of multiple related organic anion transporter (OAT) genes, have its molecular underpinnings begun to be explored. Several excellent and detailed recent reviews have addressed substrates, regulation, physiology, and clinical correlates of the cloned OATs (Berkhin and Humphreys, 2001;Dresser et al, 2001;Sweet et al, 2001;Dantzler, 2002;Russel et al, 2002;You, 2002;Eraly et al, 2003a;Terlouw et al, 2003). Here, we focus on the molecular biology and pharmacology of OATs, particularly in relation to genomic location, transcriptional regulation, protein structure, ontogeny, knockouts, toxicology, and pharmacogenetics.…”