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

2007; American Society for Pharmacology and Experimental Therapeutics; Volume: 323; Issue: 2 Linguagem: Inglês

10.1124/jpet.107.128603

1521-0103

Voula Gaganis, John O. Miners, James S. Brennan, Anthony J. Thomas, Kathleen Knights,

Eicosanoids and Hypertension Pharmacology

There is currently little information regarding the localization of UDP-glucuronosyltransferases (UGTs) in human renal cortex and medulla, and the functional contribution of renal UGTs to drug glucuronidation remains poorly defined. Using human kidney sections and human kidney cortical microsomes (HKCM) and human kidney medullary microsomes (HKMM), we combined immunohistochemistry to investigate UGT1A and UGT2B7 expression with in vitro microsomal studies to determine the kinetics of S -naproxen acyl glucuronidation. With the exception of the glomerulus, Bowman9s capsule, and renal vasculature, UGT1A proteins and UGT2B7 were expressed throughout the proximal and distal convoluted tubules, the loops of Henle, and the collecting ducts. Additionally, UGT1A and UGT2B7 expression was demonstrated in the macula densa, supporting a potential role of UGTs in regulating aldosterone. Consistent with the immunohistochemical data, S -naproxen acyl glucuronidation was catalyzed by HKCM and HKMM. Kinetic data were well described by the two-enzyme Michaelis-Menten equation. K m values for the high-affinity components were 34 ± 14 μM (HKCM) and 45 ± 14 μM (HKMM). Fluconazole inhibited the high-affinity component establishing UGT2B7 as the enzyme responsible for S -naproxen glucuronidation in cortex and medulla. The low-affinity component was relatively unaffected by fluconazole (<15% inhibition), supporting the presence of other UGTs with S -naproxen glucuronidation capacity (e.g., UGT1A6 and UGT1A9) in cortex and medulla. We postulate that the ubiquitous distribution of UGTs in mammalian kidney may buffer physiological responses to endogenous mediators, but at the same time competitive xenobiotic-endobiotic interactions may provide an explanation for the adverse renal effects of drugs, including nonsteroidal anti-inflammatory drugs.