Malaria and uric acid

Uric acid and hypoxanthine: emerging as key factor in malaria

lutgenp Blood of Plasmodium falciparum-infected persons contains large quantities of uric acid precipitates. Uric acid precipitates are highly inflammatory molecules that are considered a danger signal for innate immunity and are the causative agent of gout. Uric acid may also be beneficial: it has an extraordinary ability to scavenge radicals in the plasma and extracellular environment protecting cells from external oxidative stress. Entry of uric acid into the cells has an opposite pro-oxidant effect. Sautin YY, Johnson RJ, Uric acid: The oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids. 2008 June ; 27(6): 608–619. doi:10.1080/15257770802138558. Malaria parasites, unable to synthesize purine de novo, use host derived hypoxanthine preferentially as purine source. Hypoxanthine is a degradation product of ATP (adenosine triphosphate). Xanthine oxidase is an enzyme that generates reactive oxygen species. In mammalian tissues the enzyme is distributed widely, high levels being found in liver and intestine. Parks DA, Granger DN. Xanthine oxidase: biochemistry, distribution and physiology. Acta Physiol Scand Suppl. 1986;548:87-99. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid. These enzymes play an important role in the catabolism of purines in some species, including humans. The enzyme has broad substrate specificity and is capable to generate the reactive oxygen species (ROS), superoxide and hydrogen peroxide. It can also reduce nitrite, yielding reactive nitrogen species (RNS), such as nitric oxide and peroxynitrite. By virtue of its capacity to generate ROS and RNS, milk XOR may play an antimicrobial defensive role in the neonatal gut. Roger Harrison. Milk xanthine oxidase: Properties and physiological roles. International Dairy Journal, 2006, 16, 546-554 Formula-fed babies contract gastroenteritis more than breast-fed babies, which is of concern to mothers who cannot breastfeed or, as with HIV-infected mothers, are discouraged from breastfeeding. The ability of endogenous breastmilk xanthine oxidase to generate the antimicrobial radical nitric oxide has been measured and its influence on the growth of Escherichia coli and Salmonella enteritides examined. Breastmilk, but not formula feed, generated nitric oxide. Xanthine oxidase activity substantially inhibited the growth of both bacteria. An important natural antibiotic system is missing in formula feeds; the addition of xanthine oxidase may improve formula for use when breastfeeding is not a safe option. Stevens CR, Millar TM, Clinch JG, Kanczler JM, Bodamyali T, Blake DR. Antibacterial properties of xanthine oxidase in human milk. Lancet. 2000 Sep 2;356(9232):829-30. Uric acid may function either as antioxidant or pro-oxidant. Urate is capable to scavenge oxygen radicals. Uric acid can also form free radicals, like peroxynitrite. Y Sautin, R Johnson. Uric acid: the oxidant-antioxidant paradox. Nucleosisides Nucleotides Nucleic Acids 2008, 27, 608-619. Hypoxanthine concentration in Plasmodium infected erythrocytes is much higher than in uninfected ones Berman P, Human L. Regulation of hypoxanthine uptake and release in human erythrocytes, 1990, J Biol Chem 265, 6562-68. Supplementation of a culture medium with 100-400µM hypoxanthine increases parasite yields three- to fourfold. Zolg JW, MacLeod AJ, Dickson IH, Scaife JG. Plasmodium falciparum: modifications of the in vitro culture conditions improving parasitic yields. J Parasitol. 1982 Dec;68(6):1072-80. Cape Town university investigated the ability of xanthine oxidase to inhibit Plasmodium falciparum growth in vitro in human erythrocytes. They observed a 90% inhibition after 72 hours of incubation in 20 mU/ml xanthine oxidase. Inhibition was reversed by excess hypoxanthine. The data confirm that that a supply of host-derived hypoxanthine is critical for nucleic acid synthesis in Plasmodium falciparum and that depletion of this hypoxanthine pool with xanthine oxidase offers a novel approach for malaria treatment in humans. P Berman, L Human, J Freese. Xanthine oxidase inhibits growth of Plasmodium falciparum. J Clin Invest, 1991, 88, 1848-1855. Julio Gallego-Delgado, Maureen TyJamie M. Orengo Diana van de Hoef, Ana Rodriguez. A Surprising Role for Uric Acid: The Inflammatory Malaria Response. Current Rheumatology Reports February 2014, 16:401 But these findings from Cape Town might be misleading. The results are based on 72 hours of in vitro incubation. Previous results had shown that xanthine oxidase is absent from the food vacuole and the infected erythrocyte. The total levels of uric acid (soluble and precipitates) are similar in both P. falciparum-infected and uninfected erythrocytes, It’s action is thus limited to the excess of hypoxanthine released from the ruptured erythrocyte and transformed into uric acid. Reyes P, Rathod PK, Sanchez DJ, Heidrich HG, Enzymes of purine and pyrimidine metabolism from the human malaria parasite, Plasmodium falciparum. Mol Biochem Parasitol 1982, 5, 275-90 At rupture of the schizonts, uric acid precipitates are released into the blood stream and into micro-vessels and stimulate immune cells to produce inflammatory cytokines IL-6, Il-8 and TNF-alpha. Lopera T, Diana L. van de Hoef, Saibou Doumbia, Ana Rodriguez, Jennifer M. Anderson, Uric Acid Levels Correlatewith Inflammation and Disease Severity in Malian Children with Plasmodium falciparum Malaria PLOS, 2012, 7;10 doi.org/10.1371/journal.pone.0046424 Since the inflammatory reaction induced by Plasmodium falciparum is considered a major cause of malaria pathogenesis, identifying the mechanisms used by the parasite is essential for the development of new drugs. It has for example been demonstrated that the incubation with immune erythrocytes reduced parasite maturation and decreased parasite multiplication in a dose dependant manner. Preeyaporn Monatrakul, Mathirut Mungthin, Arjen M Dondorp, Srivicha Krudsood, Rachanee Udomsangpetch, Polrat Wilairatana, Nicholas J White and Kesinee Chotivanich. Modulating effects of plasma containing anti-malarial antibodies on in vitro anti-malarial drug susceptibility in Plasmodium falciparum. Malaria Journal20109:326 DOI: 10.1186/1475-2875-9-326 The control of uric acid may offer the possibility for the development of new antimalarial drugs. Uric acid precipitates induce maturation of human dendritic cells. Diana L. van de Hoef, Isabelle Coppens, Thomas Holowka, Choukri Ben Mamoun, OraLee Branch, and Ana Rodriguez. Plasmodium falciparum-Derived Uric Acid Precipitates Induce Maturation of Dendritic Cells. PLoS One. 2013; 8(2): e55584. Allopurinol, the common drug used against gout, inhibits the xanthine oxidase which transforms hypoxanthine into xanthine. This same drug also reduces the inflammatory interleukines, TNF, IL-6, IL-8 released by Plasmodium falciparum. Allopurinol showed a faster decrease in fever and splenomegaly compared to patients treated with quinine alone, even though parasite levels decreased at a similar rate in both groups Orengo JM, Leliwa-Sytek A, Evans JE, Evans B, van de Hoef D, Nyako M, et al. (2009) Uric Acid Is a Mediator of the Plasmodium falciparum-Induced Inflammatory Response. PLoS ONE 4(4): e5194. doi:10.1371/journal.pone.0005194 Several flavonoids like rutin, kaempferol, naringenin, luteolin, quercetin inhibit xanthine oxidase and reduce serum uric acid levels, but more in vitro than in vivo. Huang J, Wang S, Zhu M, Chen J, Zhu X. Effects of genistein, apigenin, quercetin, rutin and astilbin on serum uric acid levels and xanthine oxidase activities in normal and hyperuricemic mice. Food Chem Toxicol. 2011 Sep;49(9):1943-7. doi: 10.1016/j.fct.2011.04.029. Mo SF, Zhou F, Lv YZ, Hu QH, Zhang DM, Kong LD. Hypouricemic action of selected flavonoids in mice: structure-activity relationships. Biol Pharm Bull. 2007 Aug;30(8):1551-6. A Nagao, M Seki, H Kobayashi, Inhibition of xanthine oxidase by flavonoids. Biosci Biotechnol Biochem, 1999, 63, 1787-90. Procyanidins and proanthocyanidins show a higher activity. Catechins show no activity. Wang Y, Zhu JX, Kong LD, Yang C, Cheng CH, Zhang X. Administration of procyanidins from grape seeds reduces serum uric acid levels and decreases hepatic xanthine dehydrogenase/oxidase activities in oxonate-treated mice. Basic Clin Pharmacol Toxicol. 2004 May;94(5):232-7. Quercetin protects against renal uric acid disorder. Ju Wang, Ying Pan, Ye Hong, Qing-Yu Zhang, Xiao-Ning Wang, and Ling-Dong Kong . Quercetin Protects against Cadmium-Induced Renal Uric Acid Transport System Alteration and Lipid Metabolism Disorder in Rats. Evid Based Complement Alternat Med. 2012; doi: 10.1155/2012/548430 Another study compared the inhibition of bovine xanthine oxidase of several natural compounds and found that luteolin had the strongest action. Contrary to previous reports curcumin had none. James M. Pauff and Russ Hille. Inhibition Studies of Bovine Xanthine Oxidase by Luteolin, Silibinin, Quercetin, and Curcumin. J Nat Prod. 2009 Apr; 72(4): 725–731. doi: 10.1021/np8007123 A Vietnamese study even found that luteolin was more potent than allopurinol i.e. had a 2times lower IC50. Nguyen MT, Awale S, Tezuka Y, Tran QL, Watanabe H, Kadota S. Xanthine oxidase inhibitory activity of Vietnamese medicinal plants. Biol Pharm Bull. 2004 Sep;27(9):1414-21. Yan J, Zhang G, Hu Y, Ma Y. Effect of luteolin on xanthine oxidase: inhibition kinetics and interaction mechanism merging with docking simulation. Food Chem. 2013 Dec 15;141(4):3766-73. doi: 10.1016/j.foodchem.2013.06.092 and eventually explains the strong antimalarial properties of Artemisia afra rich in luteolin. Other Asteraceae like Chrysanthemum sinense containind dicaffeoylquinic acid also have an hypouricemic effect. MT Nguyen, S Awale, Hypouricemic Effects of Acacetin and 4,5-o-Dicaffeoylquinic acid . Biol Pharm Bull 2005, 28, 2231-2234. Saponins present in Artemisia plants have ammonia-binding activity. When ammonia is processed by the liver, uric acid is created. Saponins cause notable delays in uric acid crystallization. They accelerate the excretion of uric acid. Chen GL, Wei W, Xu SY. Effect and mechanism of total saponin of Dioscorea on animal experimental hyperuricemia. Am J Chin Med. 2006;34(1):77-85. Furosemide (Lasix) another diuretic agent is able to inhibit hypoxanthine (a necessary nitrogen source for bacteria and parasites) uptake. But most antimalarials also show this effect. The incorporation of radiolabeled hypoxanthine is one of the most reliable test for malaria drug research. Hydroxydavanone, a molecule present in Artemisia afra at concentration 0.1-1.0 ng had an inhibitory effect stronger than artemisinin, and much stronger than chloroquine or mefloquine. In South Africa it was found that the essential oil nerolidol had a stronger inhibition of hypoxanthine incorporation than quinine. ST Seatlholo, The biological activity of specific essential oil constituents, Dissertation, University of Witwatersrand, 2007. Saponins cause notable delays in uric acid crystallization. They accelerate the excretion. Chen GL, Wei W, Xu SY.Effect and mechanism of total saponin of Dioscorea on animal experimental hyperuricemia. Am J Chin Med. 2006;34(1):77-85. Sulfated polysaccharides like fucoidan also reduce uric lithogenesis. Coothan Kandaswamy Veena, Anthony Josephine, Sreenivasan P Preetha, Nachiappa Ganesh Rajesh, Palaninathan Varalakshmi. Mitochondrial dysfunction in an animal model of hyperoxaluria: a prophylactic approach with fucoidan. Eur J Pharmacol 2008 Jan 16;579(1-3):330-6. Polysaccharides inhibit the sodium urate crystal adherence to bladder surface (CL Parsons et al., J Urol 134, 614-16, 1985). Noni is a fruit extensively used against gout. It is very rich in scopoletin. This coumarin inhibits the xanthine oxidase. Palu A, Deng S, West B, Jensen J. Xanthine oxidase inhibiting effects of noni (Morinda citrifolia) fruit juice. Phytother Res. 2009 Dec;23(12):1790-1. doi: 10.1002/ptr.2842. and the monosodium urate crystal induced inflammation. Yao X, Ding Z, Xia Y, Wei Z, Luo Y, Feleder C, et al. Inhibition of monosodium urate crystal-induced inflammation by scopoletin and underlying mechanisms. Int Immunopharmacol. (2012) 14: 454–462. doi: 10.1016/j.intimp.2012.07.024 Stems of Artemisia annua are relatively richer in scopoletin than leaves Process for the isolation of compound scopoletin useful as nitric oxide synthesis inhibitor. US 6337095 B1 Esculetin, another coumarin, was found to be even more potent as inhibitor. Lin HC, Tsai SH, Chen CS, Chang YC, Lee CM, Lai ZY, Lin CM. Structure-activity relationship of coumarin derivatives on xanthine oxidase-inhibiting and free radical-scavenging activities. Biochem Pharmacol. 2008 Mar 15;75(6):1416-25. doi: 10.1016/j.bcp.2007.11.023. Hydrophilic ester-bearing chlorogenic acid binds to a novel domain to inhibit xanthine oxidase. Shwu-Huey SH Wang, Chien-Shu CS Chen, Shih-Hao SH Huang, Szu-Hsu SH Yu, Chlorogenic acid is also a strong inhibitor of xanthine oxidase. Planta medica 31 Mar '09 MT Nguyen, S Awale, Hypouremic effects of Dicaffeoylquinic acid Biol Pharm Bull, 2005, 28 2231-2234 The role of chlorogenic acid and its dicaffeoylquinic analogs in Artemisia annua has probably been ignored because this hydrophilic molecule hardly dissolves in the organic solvents used in most of the studies. The University of Louvain has shown that it is present in Artemisia annua infusions, often at concentrations much higher than artemisinin. PM de Magalhães, I Dupont, A Hendrickx, A Joly, T Raas, S Dessy, Anti-inflammatory effect and modulation of cytochrome P450 activities by Artemisia annua tea infusions in human intestinal Caco-2 cells. Food chemistry 134 (2), 864-871 Recently the University of Leiden Mouton J, Jansen O, Frédérich M, van der Kooy F. Is artemisinin the only antiplasmodial compound in the Artemisia annua tea infusion? An in vitro study. Planta Med. 2013 Apr;79(6):468-70. doi: 10.1055/s-0032-1328324. has confirmed that it is well present in Artemisia annua tea infusions. Its concentration is sometimes higher in stems than in leaves Its concentration in many plants increases with storage time. Amoo SO, Aremu AO, Moyo M, Van Staden J. Antioxidant and acetylcholinesterase-inhibitory properties of long-term stored medicinal plants. BMC Complement Altern Med. 2012 Jul 7;12:87. doi: 10.1186/1472-6882-12-87. Chlorogenic acid has strong antioxidant properties which might counteract the ROS generated by xanthine oxidase or by artemisinin and its derivatives.

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