Human Renal Cortical and Medullary UDP-Glucuronosyltransferases (UGTs): Immunohistochemical Localization of UGT2B7 and UGT1A Enzymes and Kinetic Characterization of S-Naproxen Glucuronidation

摘要: There is currently little information regarding the localization of UDP-glucuronosyltransferases (UGTs) in human renal cortex and medulla, functional contribution UGTs to drug glucuronidation remains poorly defined. Using kidney sections cortical microsomes (HKCM) medullary (HKMM), we combined immunohistochemistry investigate UGT1A UGT2B7 expression with vitro microsomal studies determine kinetics S-naproxen acyl glucuronidation. With exception glomerulus, Bowman's capsule, vasculature, proteins were expressed throughout proximal distal convoluted tubules, loops Henle, collecting ducts. Additionally, was demonstrated macula densa, supporting a potential role regulating aldosterone. Consistent immunohistochemical data, catalyzed by HKCM HKMM. Kinetic data well described two-enzyme Michaelis-Menten equation. K(m) values for high-affinity components 34 +/- 14 microM 45 (HKMM). Fluconazole inhibited component establishing as enzyme responsible medulla. The low-affinity relatively unaffected fluconazole (<15% inhibition), presence other capacity (e.g., UGT1A6 UGT1A9) We postulate that ubiquitous distribution mammalian may buffer physiological responses endogenous mediators, but at same time competitive xenobiotic-endobiotic interactions provide an explanation adverse effects drugs, including nonsteroidal anti-inflammatory drugs.