Inhibition of urease-mediated ammonia production by 2-octynohydroxamic acid in hepatic encephalopathy.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 Mar 2024
12 Mar 2024
Historique:
received:
23
06
2023
accepted:
28
02
2024
medline:
13
3
2024
pubmed:
13
3
2024
entrez:
13
3
2024
Statut:
epublish
Résumé
Hepatic encephalopathy is a neuropsychiatric complication of liver disease which is partly associated with elevated ammonemia. Urea hydrolysis by urease-producing bacteria in the colon is often mentioned as one of the main routes of ammonia production in the body, yet research on treatments targeting bacterial ureases in hepatic encephalopathy is limited. Herein we report a hydroxamate-based urease inhibitor, 2-octynohydroxamic acid, exhibiting improved in vitro potency compared to hydroxamic acids that were previously investigated for hepatic encephalopathy. 2-octynohydroxamic acid shows low cytotoxic and mutagenic potential within a micromolar concentration range as well as reduces ammonemia in rodent models of liver disease. Furthermore, 2-octynohydroxamic acid treatment decreases cerebellar glutamine, a product of ammonia metabolism, in male bile duct ligated rats. A prototype colonic formulation enables reduced systemic exposure to 2-octynohydroxamic acid in male dogs. Overall, this work suggests that urease inhibitors delivered to the colon by means of colonic formulations represent a prospective approach for the treatment of hepatic encephalopathy.
Identifiants
pubmed: 38472276
doi: 10.1038/s41467-024-46481-8
pii: 10.1038/s41467-024-46481-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2226Informations de copyright
© 2024. The Author(s).
Références
Vilstrup, H. et al. Hepatic encephalopathy in chronic liver disease: 2014 practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver. Hepatology 60, 715–735 (2014).
pubmed: 25042402
doi: 10.1002/hep.27210
Rose, C. F. et al. Hepatic encephalopathy: Novel insights into classification, pathophysiology and therapy. J. Hepatol. 73, 1526–1547 (2020).
pubmed: 33097308
doi: 10.1016/j.jhep.2020.07.013
Hirode, G., Vittinghoff, E. & Wong, R. J. Increasing burden of hepatic encephalopathy among hospitalized adults: an analysis of the 2010-2014 National Inpatient Sample. Dig. Dis. Sci. 64, 1448–1457 (2019).
pubmed: 30863953
doi: 10.1007/s10620-019-05576-9
Cheemerla, S. & Balakrishnan, M. Global epidemiology of chronic liver disease. Clin. Liver Dis. 17, 365–370 (2021).
doi: 10.1002/cld.1061
Aldridge, D. R., Tranah, E. J. & Shawcross, D. L. Pathogenesis of hepatic encephalopathy: Role of ammonia and systemic inflammation. J. Clin. Exp. Hepatol. 5, 7–20 (2015).
doi: 10.1016/j.jceh.2014.06.004
Walker, V. Ammonia metabolism and hyperammonemic disorders. In Advances in Clinical Chemistry (ed. Makowski, G. S.) 67 73–150 (Makowski G. S., 2014).
Häberle, J. Clinical and biochemical aspects of primary and secondary hyperammonemic disorders. Arch. Biochem. Biophys. 536, 101–108 (2013).
pubmed: 23628343
doi: 10.1016/j.abb.2013.04.009
Wright, G., Noiret, L., Damink, S. W. M. O. & Jalan, R. Interorgan ammonia metabolism in liver failure: the basis of current and future therapies. Liver Int 31, 163–175 (2011).
pubmed: 20673233
doi: 10.1111/j.1478-3231.2010.02302.x
Braissant, O., McLin, V. A. & Cudalbu, C. Ammonia toxicity to the brain. J. Inherit. Metab. Dis. 36, 595–612 (2013).
pubmed: 23109059
doi: 10.1007/s10545-012-9546-2
Pierzchala, K. et al. Central nervous system and systemic oxidative stress interplay with inflammation in a bile duct ligation rat model of type C hepatic encephalopathy. Free Radic. Biol. Med. 178, 295–307 (2022).
pubmed: 34890769
doi: 10.1016/j.freeradbiomed.2021.12.011
Bajaj, J. S., Sanyal, A. J., Bell, D., Gilles, H. & Heuman, D. M. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment. Pharmacol. Ther. 31, 1012–1017 (2010).
pubmed: 20136802
doi: 10.1111/j.1365-2036.2010.04257.x
Matoori, S. & Leroux, J.-C. Recent advances in the treatment of hyperammonemia. Adv. Drug Deliv. Rev. 90, 55–68 (2015).
pubmed: 25895618
doi: 10.1016/j.addr.2015.04.009
Bajaj, J. S. Review article: potential mechanisms of action of rifaximin in the management of hepatic encephalopathy and other complications of cirrhosis. Aliment. Pharmacol. Ther. 43, 11–26 (2016).
pubmed: 26618922
doi: 10.1111/apt.13435
Kimer, N., Krag, A., Møller, S., Bendtsen, F. & Gluud, L. L. Systematic review with meta-analysis: the effects of rifaximin in hepatic encephalopathy. Aliment. Pharmacol. Ther. 40, 123–132 (2014).
pubmed: 24849268
doi: 10.1111/apt.12803
Calanni, F., Renzulli, C., Barbanti, M. & Viscomi, G. C. Rifaximin: beyond the traditional antibiotic activity. J. Antibiot. (Tokyo) 67, 667–670 (2014).
pubmed: 25095806
doi: 10.1038/ja.2014.106
Jiang, Z. D. & DuPont, H. L. Rifaximin: in vitro and in vivo antibacterial activity-a review. Chemotherapy 51, 67–72 (2005).
pubmed: 15855749
doi: 10.1159/000081991
Walser, M. Determinants of ureagenesis, with particular reference to renal failure. Kidney Int 17, 709–721 (1980).
pubmed: 6997590
doi: 10.1038/ki.1980.84
Mazzei, L., Musiani, F. & Ciurli, S. The structure-based reaction mechanism of urease, a nickel dependent enzyme: tale of a long debate. J. Biol. Inorg. Chem. 25, 829–845 (2020).
pubmed: 32809087
pmcid: 7433671
doi: 10.1007/s00775-020-01808-w
Kappaun, K., Piovesan, A. R., Carlini, C. R. & Ligabue-Braun, R. Ureases: historical aspects, catalytic, and non-catalytic properties – a review. J. Adv. Res. 13, 3–17 (2018).
pubmed: 30094078
pmcid: 6077230
doi: 10.1016/j.jare.2018.05.010
Mazzei, L. & Ciurli, S. Urease. In Encyclopedia of Inorganic and Bioinorganic Chemistry 1–11 (John Wiley & Sons, Ltd). https://doi.org/10.1002/9781119951438.eibc2776 . (2021).
Krajewska, B. & Ureases, I. Functional, catalytic and kinetic properties: a review. J. Mol. Catal. B Enzym. 59, 9–21 (2009).
doi: 10.1016/j.molcatb.2009.01.003
Begum, A., Choudhary, M. I. & Betzel, C. The first Jack bean urease (Canavalia ensiformis) complex obtained at 1.52 resolution. https://doi.org/10.2210/pdb4h9m/pdb (2012).
Benini, S. et al. The complex of Bacillus pasteurii urease with acetohydroxamate anion from X-ray data at 1.55 Å resolution. JBIC J. Biol. Inorg. Chem. 5, 110–118 (2000).
pubmed: 10766443
doi: 10.1007/s007750050014
Benini, S., Rypniewski, W. R., Wilson, K. S., Ciurli, S. & Mangani, S. Structure of Bacillus Pasteurii urease inhibited with acetohydroxamic acid at 1.55 A resolution. https://doi.org/10.2210/pdb4ubp/pdb (1999).
Ha, N.-C. et al. Supramolecular assembly and acid resistance of Helicobacter pylori urease. Nat. Struct. Biol. 8, 505–509 (2001).
pubmed: 11373617
doi: 10.1038/88563
Ha, N.-C., Oh, S.-T. & Oh, B.-H. Crystal structure of Helicobacter pylori urease in complex with acetohydroxamic acid. https://doi.org/10.2210/pdb1e9y/pdb (2000).
Pearson, M. A., Michel, L. O., Hausinger, R. P. & Karplus, P. A. Structures of Cys319 Variants and Acetohydroxamate-Inhibited Klebsiella aerogenes Urease. Biochemistry 36, 8164–8172 (1997).
pubmed: 9201965
doi: 10.1021/bi970514j
Pearson, M. A. & Karplus, P. A. Klebsiella Aerogenes urease, C319A variant with acetohydroxamic acid (AHA) bound. https://doi.org/10.2210/pdb1fwe/pdb (1997).
Cunha, E. S., Chen, X., Sanz-Gaitero, M., Mills, D. J. & Luecke, H. Cryo-EM structure of Helicobacter pylori urease with an inhibitor in the active site at 2.0 Å resolution. Nat. Commun. 12, 230 (2021).
pubmed: 33431861
pmcid: 7801526
doi: 10.1038/s41467-020-20485-6
Luecke, H. & Cunha, E. Helicobacter pylori urease with inhibitor bound in the active site. https://doi.org/10.2210/pdb6zja/pdb (2020).
Fishbein, W. N., Carbone, P. P. & Hochstein, H. D. Acetohydroxamate: bacterial urease inhibitor with therapeutic potential in hyperammonaemic states. Nature 208, 46–48 (1965).
pubmed: 5886683
doi: 10.1038/208046a0
Summerskill, W. H. J., Thorsell, F., Feinberg, J. H. & Aldrete, J. S. Effects of urease inhibition in hyperammonemia: clinical and experimental studies with acetohydroxamic acid. Gastroenterology 54, 20–26 (1968).
pubmed: 5635434
doi: 10.1016/S0016-5085(68)80032-0
Takahashi, T. et al. Effect of caprylohydroxamic acid upon the blood ammonia levels in man and dogs. Gastroenterol. Jpn. 2, 236–236 (1967).
doi: 10.1007/BF02801701
Kashimura, K. Experimental and clinical studies on the effect of urease inhibitor on hyperammoniemia. Kanzo 15, 172–185 (1974).
doi: 10.2957/kanzo.15.172
Hirayama, C. et al. A controlled clinical trial of nicotinohydroxamic acid and neomycin in advanced chronic liver disease. Digestion 25, 115–123 (1982).
pubmed: 6217100
doi: 10.1159/000198819
Kobashi, K., Kumaki, K. & Hase, J. Effect of acyl residues of hydroxamic acids on urease inhibition. Biochim. Biophys. Acta BBA - Enzymol. 227, 429–441 (1971).
doi: 10.1016/0005-2744(71)90074-X
Hase, J. & Kobashi, K. Inhibition of Proteus vulgaris urease by hydroxamic acids. J. Biochem. (Tokyo) 62, 293–299 (1967).
pubmed: 5586497
Shen, S. & Kozikowski, A. P. Why hydroxamates may not be the best histone deacetylase inhibitors—what some may have forgotten or would rather forget? ChemMedChem. 11, 15–21 (2016).
pubmed: 26603496
doi: 10.1002/cmdc.201500486
Langerholc, T., Maragkoudakis, P. A., Wollgast, J., Gradisnik, L. & Cencic, A. Novel and established intestinal cell line models – An indispensable tool in food science and nutrition. Trends Food Sci. Technol. 22, S11–S20 (2011).
pubmed: 32336880
pmcid: 7172287
doi: 10.1016/j.tifs.2011.03.010
Ching Yung Wang Mutagenicity of hydroxamic acids for Salmonella typhimurium. Mutat. Res. Mol. Mech. Mutagen. 56, 7–12 (1977).
doi: 10.1016/0027-5107(77)90235-4
Ohta, T. et al. Mutagenicity screening of feed additives in the microbial system. Mutat. Res. 77, 21–30 (1980).
pubmed: 6767184
doi: 10.1016/0165-1218(80)90116-0
Ziegler-Slylakakis, K., Schwarz, L. R. & Andrae, U. Microsome- and hepatocyte-mediated mutagenicity of hydroxyurea and related aliphatic hydroxamic acids in V79 Chinese hamster cells. Mutat. Res. Mol. Mech. Mutagen. 152, 225–231 (1985).
doi: 10.1016/0027-5107(85)90065-X
Wang, C. Y. & Lee, L. H. Mutagenicity and Antibacterial Activity of Hydroxamic Acids. Antimicrob. Agents Chemother. 11, 753–755 (1977).
pubmed: 856029
pmcid: 352062
doi: 10.1128/AAC.11.4.753
Skipper, P. L., Tannenbaum, S. R., Thilly, W. G., Furth, E. E. & Bishop, W. W. Mutagenicity of hydroxamic acids and the probable involvement of carbamoylation. Cancer Res 40, 4704–4708 (1980).
pubmed: 7002295
Zhu, C., Jiang, L., Chen, T.-M. & Hwang, K.-K. A comparative study of artificial membrane permeability assay for high throughput profiling of drug absorption potential. Eur. J. Med. Chem. 37, 399–407 (2002).
pubmed: 12008054
doi: 10.1016/S0223-5234(02)01360-0
Song, Y., Peressin, K., Wong, P. Y., Page, S. W. & Garg, S. Key considerations in designing oral drug delivery systems for dogs. J. Pharm. Sci. 105, 1576–1585 (2016).
pubmed: 27056627
doi: 10.1016/j.xphs.2016.03.007
McConnell, E. L., Basit, A. W. & Murdan, S. Measurements of rat and mouse gastrointestinal pH, fluid and lymphoid tissue, and implications for in-vivo experiments. J. Pharm. Pharmacol. 60, 63–70 (2008).
pubmed: 18088506
doi: 10.1211/jpp.60.1.0008
Quini, C. C. et al. Employment of a noninvasive magnetic method for evaluation of gastrointestinal transit in rats. J. Biol. Eng. 6, 6 (2012).
pubmed: 22587220
pmcid: 3412735
doi: 10.1186/1754-1611-6-6
Mukherjee, D. & Ahmad, R. Dose-dependent effect of N’-Nitrosodiethylamine on hepatic architecture, RBC rheology and polypeptide repertoire in Wistar rats. Interdiscip. Toxicol. 8, 1–7 (2015).
pubmed: 27486353
pmcid: 4961919
doi: 10.1515/intox-2015-0001
Tolba, R., Kraus, T., Liedtke, C., Schwarz, M. & Weiskirchen, R. Diethylnitrosamine (DEN)-induced carcinogenic liver injury in mice. Lab. Anim. 49, 59–69 (2015).
pubmed: 25835739
doi: 10.1177/0023677215570086
DeMorrow, S., Cudalbu, C., Davies, N., Jayakumar, A. R. & Rose, C. F. 2021 ISHEN guidelines on animal models of hepatic encephalopathy. Liver Int 41, 1474–1488 (2021).
pubmed: 33900013
pmcid: 9812338
doi: 10.1111/liv.14911
Flatt, E. et al. Probiotics combined with rifaximin influence the neurometabolic changes in a rat model of type C HE. Sci. Rep. 11, 17988 (2021).
pubmed: 34504135
pmcid: 8429411
doi: 10.1038/s41598-021-97018-8
Mosso, J. et al. PET CMRglc mapping and 1H-MRS show altered glucose uptake and neurometabolic profiles in BDL rats. Anal. Biochem. 647, 114606 (2022).
pubmed: 35240109
doi: 10.1016/j.ab.2022.114606
Braissant, O. et al. Longitudinal neurometabolic changes in the hippocampus of a rat model of chronic hepatic encephalopathy. J. Hepatol. 71, 505–515 (2019).
pubmed: 31173812
doi: 10.1016/j.jhep.2019.05.022
Rackayova, V. et al. 1H and 31P magnetic resonance spectroscopy in a rat model of chronic hepatic encephalopathy: in vivo longitudinal measurements of brain energy metabolism. Metab. Brain Dis. 31, 1303–1314 (2016).
pubmed: 26253240
doi: 10.1007/s11011-015-9715-8
Córdoba, J., Gottstein, J. & Blei, A. T. Glutamine, myo-inositol, and organic brain osmolytes after portocaval anastomosis in the rat: Implications for ammonia-induced brain edema. Hepatology 24, 919–923 (1996).
pubmed: 8855198
Chavarria, L. & Cordoba, J. Magnetic resonance of the brain in chronic and acute liver failure. Metab. Brain Dis. 29, 937–944 (2014).
pubmed: 24254992
doi: 10.1007/s11011-013-9452-9
Cordoba, J. Glutamine, myo-inositol, and brain edema in acute liver failure. Hepatology 23, 1291–1292 (1996).
pubmed: 8621171
doi: 10.1002/hep.510230557
Rackayová, V. et al. Probiotics improve the neurometabolic profile of rats with chronic cholestatic liver disease. Sci. Rep. 11, 2269 (2021).
pubmed: 33500487
pmcid: 7838316
doi: 10.1038/s41598-021-81871-8
Cauli, O. et al. Glutamatergic and gabaergic neurotransmission and neuronal circuits in hepatic encephalopathy. Metab. Brain Dis. 24, 69–80 (2009).
pubmed: 19085094
doi: 10.1007/s11011-008-9115-4
Rackayova, V., Braissant, O., Rougemont, A.-L., Cudalbu, C. & McLin, V. A. Longitudinal osmotic and neurometabolic changes in young rats with chronic cholestatic liver disease. Sci. Rep. 10, 7536 (2020).
pubmed: 32372057
pmcid: 7200786
doi: 10.1038/s41598-020-64416-3
Rae, C. D. A guide to the metabolic pathways and function of metabolites observed in human brain 1H Magnetic Resonance Spectra. Neurochem. Res. 39, 1–36 (2014).
pubmed: 24258018
doi: 10.1007/s11064-013-1199-5
Sheldrick, G. M. SHELXT – Integrated space-group and crystal-structure determination. Acta Crystallogr Found. Adv. 71, 3–8 (2015).
doi: 10.1107/S2053273314026370
Sheldrick, G. M. Crystal structure refinement with SHELXL. Acta Crystallogr C. Struct. Chem. 71, 3–8 (2015).
pubmed: 25567568
pmcid: 4294323
doi: 10.1107/S2053229614024218
Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. OLEX2: a complete structure solution, refinement and analysis program. J. Appl. Crystallogr. 42, 339–341 (2009).
doi: 10.1107/S0021889808042726
Agostoni, V. et al. Liposome-supported peritoneal dialysis for the treatment of hyperammonemia-associated encephalopathy. Adv. Funct. Mater. 26, 8382–8389 (2016).
doi: 10.1002/adfm.201603519
Learman, B. S., Brauer, A. L., Eaton, K. A. & Armbruster, C. E. A rare opportunist, Morganella morganii, decreases severity of polymicrobial catheter-associated urinary tract infection. Infect. Immun. 88, e00691–19 (2019).
pubmed: 31611275
pmcid: 6921659
doi: 10.1128/IAI.00691-19
Angelis, I. D. & Turco, L. Caco-2 cells as a model for intestinal absorption. Curr. Protoc. Toxicol. 47, 20.6.1–20.6.15 (2011).
doi: 10.1002/0471140856.tx2006s47
Tavelin, S., Gråsjö, J., Taipalensuu, J., Ocklind, G. & Artursson, P. Applications of epithelial cell culture in studies of drug transport. In Epithelial Cell Culture Protocols vol. 188 233–272 (Humana Press, New Jersey, 2002).
Hubatsch, I., Ragnarsson, E. G. E. & Artursson, P. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat. Protoc. 2, 2111–2119 (2007).
pubmed: 17853866
doi: 10.1038/nprot.2007.303
Gómez-Lado, N. et al. Gastrointestinal Tracking and Gastric Emptying of Coated Capsules in Rats with or without Sedation Using CT imaging. Pharmaceutics 12, 81 (2020).
pubmed: 31963818
pmcid: 7023106
doi: 10.3390/pharmaceutics12010081
Zhang, Y., Huo, M., Zhou, J. & Xie, S. PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput. Methods Prog. Biomed. 99, 306–314 (2010).
doi: 10.1016/j.cmpb.2010.01.007
Mitrea, S.-O., Sessa, D. & Cudalbu, C. BDL surgery protocol. Zenodo https://doi.org/10.5281/zenodo.10652104 (2024).
Račkayová, V. et al. Late post-natal neurometabolic development in healthy male rats using 1 H and 31 P magnetic resonance spectroscopy. J. Neurochem. 157, 508–519 (2021).
pubmed: 33421129
doi: 10.1111/jnc.15294
Mlynárik, V., Gambarota, G., Frenkel, H. & Gruetter, R. Localized short-echo-time proton MR spectroscopy with full signal-intensity acquisition. Magn. Reson. Med. 56, 965–970 (2006).
pubmed: 16991116
doi: 10.1002/mrm.21043
Gruetter, R. Automatic, localized in vivo adjustment of all first-and second-order shim coils. Magn. Reson. Med. 29, 804–811 (1993).
pubmed: 8350724
doi: 10.1002/mrm.1910290613
Tkác, I., Starcuk, Z., Choi, I. Y. & Gruetter, R. In vivo 1H NMR spectroscopy of rat brain at 1 ms echo time. Magn. Reson. Med. 41, 649–656 (1999).
pubmed: 10332839
doi: 10.1002/(SICI)1522-2594(199904)41:4<649::AID-MRM2>3.0.CO;2-G
Provencher, S. W. Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR Biomed. 14, 260–264 (2001).
pubmed: 11410943
doi: 10.1002/nbm.698
Cudalbu, C., Mlynárik, V. & Gruetter, R. Handling macromolecule signals in the quantification of the neurochemical profile. J. Alzheimers Dis. 31, S101–S115 (2012).
pubmed: 22543852
doi: 10.3233/JAD-2012-120100
Simicic, D. et al. In vivo macromolecule signals in rat brain 1H-MR spectra at 9.4T: Parametrization, spline baseline estimation, and T2 relaxation times. Magn. Reson. Med. 86, 2384–2401 (2021).
pubmed: 34268821
pmcid: 8596437
doi: 10.1002/mrm.28910