Aldosterone glucuronidation by human liver and kidney microsomes and recombinant UDP-glucuronosyltransferases: inhibition by NSAIDs
Open accessAbstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Carboxylic acid NSAIDs are extensively glucuronidated as either the parent drug or hydroxylated metabolites and UGT2B7 is ranked highest in terms of NSAID‐glucuronidation activity. • NSAIDs cause adverse renal effects including sodium and water retention and hyperkalaemia. • In human kidney the mineralocorticoid aldosterone is glucuronidated directly to form aldosterone 18β‐glucuronide. WHAT THIS STUDY ADDS • Human liver and kidney microsomes and UGT1A10 and UGT2B7 catalyze aldosterone18β‐glucuronidation. • Non‐selective NSAIDs inhibit renal and hepatic aldosterone18β‐glucuronidation andin vivothis may lead to elevated intra‐renal concentrations of this hormone. • Common involvement of UGT2B7 in NSAID and aldosterone glucuronidation predicates an intra‐renal NSAID‐aldosterone interaction that may explain in part the clinical observations of variable effects of NSAIDs on electrolytes, fluid retention and blood pressure. AIMS To characterize: i) the kinetics of aldosterone (ALDO) 18β‐glucuronidation using human liver and human kidney microsomes and identify the human UGT enzyme(s) responsible for ALDO 18β‐glucuronidation and ii) the inhibition of ALDO 18β‐glucuronidation by non‐selective NSAIDs. METHODS Using HPLC and LC‐MS methods, ALDO 18β‐glucuronidation was characterized using human liver (n= 6), human kidney microsomes (n= 5) and recombinant human UGT 1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B10, 2B15, 2B17 and 2B28 as the enzyme sources. Inhibition of ALDO 18β‐glucuronidation was investigated using alclofenac, cicloprofen, diclofenac, diflunisal, fenoprofen,R‐ andS‐ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid,S‐naproxen, pirprofen and tiaprofenic acid. A rank order of inhibition (IC50) was established and the mechanism of inhibition investigated using diclofenac,S‐ibuprofen, indomethacin, mefenamic acid andS‐naproxen. RESULTS ALDO 18β‐glucuronidation by hepatic and renal microsomes exhibited Michaelis‐Menten kinetics. Mean (±SD)Km,Vmaxand CLintvalues for HLM and HKCM were 509 ± 137 and 367 ± 170 µm, 1075 ± 429 and 1110 ± 522 pmol min−1 mg−1, and 2.36 ± 1.12 and 3.91 ± 2.35 µl min−1 mg−1, respectively. Of the UGT proteins, only UGT1A10 and UGT2B7 converted ALDO to its 18β‐glucuronide. All NSAIDs investigated inhibited ALDO 18β‐G formation by HLM, HKCM and UGT2B7. The rank order of inhibition (IC50) of renal and hepatic ALDO 18β‐glucuronidation followed the general trend: fenamates > diclofenac > arylpropionates. CONCLUSION A NSAID‐ALDO interactionin vivomay result in elevated intra‐renal concentrations of ALDO that may contribute to the adverse renal effects of NSAIDs and their effects on antihypertensive drug response.
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Aldosterone is preferentially 18-glucuronidated in the liver by UGT2B7 and UGT1A10.
“Aldosterone is preferentially 18-glucuronidated in the liver by UGT2B7 and UGT1A10 [223].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [223]
Cites
Human UDP-Glucuronosyltransferases: Metabolism, Expression, and Disease
Tukey, R. H., & Strassburg, C. P. (2000) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.40.1.581 · Cited by 1,525 · see citing works
Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily
Mackenzie, P. I., Walter Bock, K., Burchell, B., Guillemette, C., Ikushiro, S.-I., Iyanagi, T., Miners, J. O., Owens, I. S., & Nebert, D. W. (2005) · Pharmacogenetics and Genomics · doi:10.1097/01.fpc.0000173483.13689.56 · Cited by 821 · see citing works
Self-citationUchaipichat, V., Mackenzie, P. I., Guo, X.-H., Gardner-Stephen, D. A., Galetin, A., Houston, J. B., & Miners, J. O. (2004) · Drug Metabolism and Disposition · doi:10.1124/dmd.32.4.413 · Cited by 337 · see citing works
Self-citationRenal Toxicity of the Nonsteroidal Anti-Inflammatory Drugs
Murray, M. D., & Brater, D. C. (1993) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pa.33.040193.002251 · Cited by 295 · see citing works
Nonsteroidal Anti‐Inflammatory Drugs: Effects on Kidney Function
Whelton, A., & Hamilton, C. W. (1991) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1991.tb03743.x · Cited by 285 · see citing works
Renal Effects of COX-2-Selective Inhibitors
Brater, D. C., Harris, C. J., Redfern, J. S., & Gertz, B. J. (2001) · American Journal of Nephrology · doi:10.1159/000046212 · Cited by 263 · see citing works
Nonsteroidal anti-inflammatory drugs: Effects on kidney function
Whelton, A., & Watson, A. J. (1998) · Springer eBooks · doi:10.1007/978-94-015-9088-4_14 · Cited by 262 · see citing works
Uchaipichat, V., Mackenzie, P. I., Elliot, D. J., et al. (2005) · Drug Metabolism and Disposition · doi:10.1124/dmd.105.007369 · Cited by 248 · see citing works
Self-citationIn Vitro Analysis of Human Drug Glucuronidation and Prediction of in Vivo Metabolic Clearance
Soars, M. G., Burchell, B., & Riley, R. J. (2002) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.301.1.382 · Cited by 229 · see citing works
Miners, J. O., Knights, K., Houston, J. B., & Mackenzie, P. I. (2006) · Biochemical Pharmacology · doi:10.1016/j.bcp.2005.12.019 · Cited by 227 · see citing works
Self-citationJin, C., Miners, J. O., Lillywhite, K. J., & Mackenzie, P. I. (1993) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)10294-2 · Cited by 226 · see citing works
Self-citationRowland, A., Elliot, D. J., Williams, J. A., et al. (2006) · Drug Metabolism and Disposition · doi:10.1124/dmd.106.009340 · Cited by 224 · see citing works
Self-citationGambaro, G., & Perazella, M. A. (2003) · Journal of Internal Medicine · doi:10.1046/j.1365-2796.2003.01146.x · Cited by 223 · see citing works
Miners, J. O., Smith, P. A., Sorich, M. J., McKinnon, R. A., & Mackenzie, P. I. (2004) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.44.101802.121546 · Cited by 210 · see citing works
Self-citationStone, A. N., Mackenzie, P. I., Galetin, A., et al. (2003) · Drug Metabolism and Disposition · doi:10.1124/dmd.31.9.1086 · Cited by 206 · see citing works
Rowland, A., Knights, K., Mackenzie, P. I., & Miners, J. O. (2008) · Drug Metabolism and Disposition · doi:10.1124/dmd.108.021105 · Cited by 179 · see citing works
Self-citationUchaipichat, V., Winner, L. K., Mackenzie, P. I., et al. (2006) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2006.02588.x · Cited by 178 · see citing works
Self-citationRowland, A., Gaganis, V., Elliot, D. J., Mackenzie, P. I., Knights, K., & Miners, J. O. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.118216 · Cited by 167 · see citing works
Self-citationKing, C. (2001) · Toxicological Sciences · doi:10.1093/toxsci/61.1.49 · Cited by 159 · see citing works
Prostaglandin E2 inhibits renal collecting duct Na+ absorption by activating the EP1 receptor.
Guan, Y., Zhang, Y., BREYER, R. M., Fowler, B., Davis, L., Hébert, R., & Breyer, M. D. (1998) · Journal of Clinical Investigation · doi:10.1172/jci2872 · Cited by 142 · see citing works
McGurk, K. A., Brierley, C. H., & Burchell, B. (1998) · Biochemical Pharmacology · doi:10.1016/s0006-2952(97)00534-0 · Cited by 124 · see citing works
Boase, S., & Miners, J. O. (2002) · British Journal of Clinical Pharmacology · doi:10.1046/j.1365-2125.2002.01669.x · Cited by 120 · see citing works
Self-citationGlucuronidation of carboxylic acid containing compounds by UDP-glucuronosyltransferase isoforms
Sakaguchi, K., Green, M. D., Stock, N. S., et al. (2004) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2004.02.004 · Cited by 112 · see citing works
Soars, M. G., Riley, R. J., Findlay, K. A., Coffey, M., & Burchell, B. (2001) · PubMed · Cited by 105 · see citing works
The glucuronidation of mycophenolic acid by human liver, kidney and jejunum microsomes
Bowalgaha, K., & Miners, J. O. (2001) · British Journal of Clinical Pharmacology · doi:10.1046/j.0306-5251.2001.01487.x · Cited by 100 · see citing works
Self-citationBowalgaha, K., Elliot, D. J., Mackenzie, P. I., et al. (2005) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2005.02446.x · Cited by 100 · see citing works
Self-citationRowland, A., Elliot, D. J., Knights, K., et al. (2008) · Drug Metabolism and Disposition · doi:10.1124/dmd.107.019885 · Cited by 90 · see citing works
Self-citationTsoutsikos, P., Miners, J. O., Stapleton, A. M. F., et al. (2003) · Biochemical Pharmacology · doi:10.1016/j.bcp.2003.08.025 · Cited by 86 · see citing works
Self-citationMorgan, T. O., & Anderson, A. I. E. (2003) · Journal of Clinical Hypertension · doi:10.1111/j.1524-6175.2003.00514.x · Cited by 77 · see citing works
Bioavailability of diclofenac potassium at low doses
Hinz, B., Chevts, J., Renner, B., Wuttke, H., Rau, T., Schmidt, A., Szelenyi, I., Brune, K., & Werner, U. (2004) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2005.02226.x · Cited by 73 · see citing works
Effect of prostaglandins on renal epithelial electrolyte transport
Kokko, J. P. (1981) · Kidney International · doi:10.1038/ki.1981.82 · Cited by 63 · see citing works
Gaganis, V., Miners, J. O., & Knights, K. (2007) · Biochemical Pharmacology · doi:10.1016/j.bcp.2007.01.030 · Cited by 56 · see citing works
Self-citationMiners, J. O., Lillywhite, K. J., Matthews, A. P., Jones, M. E., & Birkett, D. (1988) · Biochemical Pharmacology · doi:10.1016/0006-2952(88)90140-2 · Cited by 55 · see citing works
Self-citationKerdpin, O., Knights, K., Elliot, D. J., et al. (2008) · Biochemical Pharmacology · doi:10.1016/j.bcp.2008.04.014 · Cited by 51 · see citing works
Self-citationGirard, C., Barbier, O., Veilleux, G., El-Alfy, M., & Bélanger, A. (2003) · Endocrinology · doi:10.1210/en.2002-0052 · Cited by 45 · see citing works
Gaganis, V., Miners, J. O., Brennan, J. S., Thomas, A., & Knights, K. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.128603 · Cited by 44 · see citing works
Self-citationBledsoe, T. J., Liddle, G. W., Riondel, A. M., et al. (1966) · Journal of Clinical Investigation · doi:10.1172/jci105339 · Cited by 40 · see citing works
Effect of magnesium hydroxide on the absorption of tolfenamic and mefenamic acids
Neuvonen, P. J., & Kivist�, K. T. (1988) · European Journal of Clinical Pharmacology · doi:10.1007/bf00558244 · Cited by 37 · see citing works
Sorich, M. J., McKinnon, R. A., Miners, J. O., et al. (2006) · Journal of Chemical Information and Modeling · doi:10.1021/ci600248e · Cited by 37 · see citing works
Self-citationSykes, M. J., Sorich, M. J., & Miners, J. O. (2006) · Journal of Chemical Information and Modeling · doi:10.1021/ci600221h · Cited by 34 · see citing works
Self-citationBroe, M. E. D., Verpooten, G. A., Bennett, W. M., et al. (2003) · Springer eBooks · doi:10.1007/1-4020-2586-6 · Cited by 34 · see citing works
Glucuronidation of diflunisal in liver and kidney microsomes of rat and man
Brunelle, F. M., & Verbeeck, R. K. (1996) · Xenobiotica · doi:10.3109/00498259609046694 · Cited by 27 · see citing works
Ragasa, R., Nakamura, E., Marrone, L., et al. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.121640 · Cited by 13 · see citing works
The lord of the ring: Mandatory role of the kidney in drug therapy of hypertension
López-Hernández, F. J., & López-Novoa, J. M. (2005) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2005.08.002 · Cited by 10 · see citing works
Comparative in vitro and in vivo bioavailability of naproxen from tablet and caplet formulations
Charles, B. G., & Mogg, G. A. G. (1994) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.2510150204 · Cited by 8 · see citing works
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Schiffer, L., Barnard, L., Baranowski, E. S., Gilligan, L. C., Taylor, A. E., Arlt, W., Shackleton, C. H. L., & Storbeck, K.-H. (2019) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2019.105439 · Cited by 450 · see citing works
“Estriol and 16α-hydroxyestrone are conjugated at the 3-hydroxygroup by UGT1A10 and at the 16α-hydroxy group by UGT2B7 [330,331].”
- Authors
- Knights, K. M., Winner, L. K., Elliot, D. J., Bowalgaha, K., & Miners, J. O.
- Affiliations
- Flinders University (AU)
- Corresponding author
- Knights, Kathleen M.
- Venue
- British Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2009-09
- Volume
- 68
- Issue
- 3
- Pages
- 402-412
- ISSN
- 0306-5251 (ISSN-L)
- 1365-2125
- PMC
- PMC2766480
- OpenAlex
- W2018530877
- Cited by
- 70
- References
- 45
- Citations by year
- 2025: 2 · 2024: 4 · 2023: 8 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 6 · 2018: 1 · 2017: 4 · 2016: 3 · 2015: 2 · 2014: 4 · 2013: 6 · 2012: 9
- FWCI
- 5.68
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- British Journal of Clinical Pharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Flinders Academic Commons (Flinders University) (submittedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- UDP-glucuronosyltransferase, UGT2B7, UGT1A10, liver microsomes, kidney microsomes, drug-drug interactions, diclofenac, ibuprofen
- MeSH terms
- Adult, Aged, Aldosterone, Anti-Inflammatory Agents, Non-Steroidal, Chromatography, High Pressure Liquid, Female, Humans, Kidney, Kinetics, Liver, Male, Microsomes, Middle Aged, Glucuronosyltransferase, Inhibitory Concentration 50, Glucuronides
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