Inibidor da araquidonato 5-lipoxigenase

Os inibidores da araquidonato 5-lipoxigenase são compostos capazes de reduzir ou bloquear a ação da enzima araquidonato 5-lipoxigenase (5-LOX), responsável por produção de leucotrienos. A superprodução de leucotrienos é uma das causas majoritárias de inflamação em pacientes com asma e rinite alérgica.^[1]

Dentre os inibidores de 5-LOX encontram-se o meclofenamato de sódio^[2] e o zileuton.^[2]^[3]

Algumas substâncias encontradas em quantidades mínimas na alimentação e em suplementos alimentares também são capazes de inibir a 5-LOX, tais como ^[2] ácido cafeico,^[2] curcumina,^[2] hiperforina^[4]^[5]^[6] e erva-de-são-joão.^[4]^[5]^[6]

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Agentes antileucotriênicos

Referências

↑ David L. Nelson, Michael M. Cox.
↑ ^a ^b ^c ^d ^e Bishayee K, Khuda-Bukhsh AR (setembro de 2013). «5-lipoxygenase antagonist therapy: a new approach towards targeted cancer chemotherapy». Acta Biochim. Biophys. Sin. (Shanghai). 45 (9): 709–719. PMID 23752617. doi:10.1093/abbs/gmt064
↑ «Zyflo (Zileuton tablets)» (PDF). United States Food and Drug Administration. Cornerstone Therapeutics Inc. junho de 2012. p. 1. Consultado em 12 de dezembro de 2014. Zileuton is a specific inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB4, LTC4, LTD4, and LTE4) formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro systems. Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients.
↑ ^a ^b http://www.hmdb.ca/metabolites/HMDB30463#enzymes |section-url= missing title (ajuda). Hyperforin. Human Metabolome Database. 3.6. University of Alberta. 30 de junho de 2013. Consultado em 12 de dezembro de 2014. Hyperforin is found in alcoholic beverages. Hyperforin is a constituent of Hypericum perforatum (St John's Wort) Hyperforin is a phytochemical produced by some of the members of the plant genus Hypericum, notably Hypericum perforatum (St John's wort). The structure of hyperforin was elucidated by a research group from the Shemyakin Institute of Bio-organic Chemistry (USSR Academy of Sciences in Moscow) and published in 1975. Hyperforin is a prenylated phloroglucinol derivative. Total synthesis of hyperforin has not yet been accomplished, despite attempts by several research groups. Hyperforin has been shown to exhibit anti-inflammatory, anti-tumor, antibiotic and anti-depressant functions (PMID 17696442 , 21751836 , 12725578 , 12018529 )
1. Arachidonate 5-lipoxygenase ...Specific function: Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes ...
2. Prostaglandin G/H synthase 1 ... General function: Involved in peroxidase activity
↑ ^a ^b de Melo MS, Quintans Jde S, Araújo AA, Duarte MC, Bonjardim LR, Nogueira PC, Moraes VR, de Araújo-Júnior JX, Ribeiro EA, Quintans-Júnior LJ (2014). «A systematic review for anti-inflammatory property of clusiaceae family: a preclinical approach». Evid Based Complement Alternat Med. 2014. 960258 páginas. PMC 4058220 . PMID 24976853. doi:10.1155/2014/960258. These researches are according to an investigation of the effect of H. perforatum on the NF-κB inflammation factor, conducted by Bork et al. (1999), in which hyperforin provided a potent inhibition of TNFα-induced activation of NF-κB [58]. Another important activity for hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase [59]. Moreover, this species attenuated the expression of iNOS in periodontal tissue, which may contribute to the attenuation of the formation of nitrotyrosine, an indication of nitrosative stress [26]. In this context, a combination of several active constituents of Hypericum species is the carrier of their anti-inflammatory activity.
↑ ^a ^b Wölfle U, Seelinger G, Schempp CM (fevereiro de 2014). «Topical application of St. John's wort (Hypericum perforatum)». Planta Med. 80 (2-3): 109–20. PMID 24214835. doi:10.1055/s-0033-1351019. Anti-inflammatory mechanisms of hyperforin have been described as inhibition of cyclooxygenase-1 (but not COX-2) and 5-lipoxygenase at low concentrations of 0.3 µmol/L and 1.2 µmol/L, respectively [52], and of PGE2 production in vitro [53] and in vivo with superior efficiency (ED50 = 1 mg/kg) compared to indomethacin (5 mg/kg) [54]. Hyperforin turned out to be a novel type of 5-lipoxygenase inhibitor with high effectivity in vivo [55] and suppressed oxidative bursts in polymorphonuclear cells at 1.8 µmol/L in vitro [56]. Inhibition of IFN-γ production, strong downregulation of CXCR3 expression on activated T cells, and downregulation of matrix metalloproteinase 9 expression caused Cabrelle et al. [57] to test the effectivity of hyperforin in a rat model of experimental allergic encephalomyelitis (EAE). Hyperforin attenuated the symptoms significantly, and the authors discussed hyperforin as a putative therapeutic molecule for the treatment of autoimmune inflammatory diseases sustained by Th1 cells.

[1] David L. Nelson, Michael M. Cox.

[MEDRS_review-2] Bishayee K, Khuda-Bukhsh AR (setembro de 2013). «5-lipoxygenase antagonist therapy: a new approach towards targeted cancer chemotherapy». Acta Biochim. Biophys. Sin. (Shanghai). 45 (9): 709–719. PMID 23752617. doi:10.1093/abbs/gmt064

[USFDA_Zileuton-3] «Zyflo (Zileuton tablets)» (PDF). United States Food and Drug Administration. Cornerstone Therapeutics Inc. junho de 2012. p. 1. Consultado em 12 de dezembro de 2014. Zileuton is a specific inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB4, LTC4, LTD4, and LTE4) formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro systems. Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients.

[Hyperforin_HMDB_5-LOX_COX1-4] ttp://www.hmdb.ca/metabolites/HMDB30463#enzymes |section-url= missing title (ajuda). Hyperforin. Human Metabolome Database. 3.6. University of Alberta. 30 de junho de 2013. Consultado em 12 de dezembro de 2014. Hyperforin is found in alcoholic beverages. Hyperforin is a constituent of Hypericum perforatum (St John's Wort) Hyperforin is a phytochemical produced by some of the members of the plant genus Hypericum, notably Hypericum perforatum (St John's wort). The structure of hyperforin was elucidated by a research group from the Shemyakin Institute of Bio-organic Chemistry (USSR Academy of Sciences in Moscow) and published in 1975. Hyperforin is a prenylated phloroglucinol derivative. Total synthesis of hyperforin has not yet been accomplished, despite attempts by several research groups. Hyperforin has been shown to exhibit anti-inflammatory, anti-tumor, antibiotic and anti-depressant functions (PMID 17696442 , 21751836 , 12725578 , 12018529 )
1. Arachidonate 5-lipoxygenase ...Specific function: Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes ...
2. Prostaglandin G/H synthase 1 ... General function: Involved in peroxidase activity

[Systematic_review_hypericum-5] Melo MS, Quintans Jde S, Araújo AA, Duarte MC, Bonjardim LR, Nogueira PC, Moraes VR, de Araújo-Júnior JX, Ribeiro EA, Quintans-Júnior LJ (2014). «A systematic review for anti-inflammatory property of clusiaceae family: a preclinical approach». Evid Based Complement Alternat Med. 2014. 960258 páginas. PMC 4058220 . PMID 24976853. doi:10.1155/2014/960258. These researches are according to an investigation of the effect of H. perforatum on the NF-κB inflammation factor, conducted by Bork et al. (1999), in which hyperforin provided a potent inhibition of TNFα-induced activation of NF-κB [58]. Another important activity for hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase [59]. Moreover, this species attenuated the expression of iNOS in periodontal tissue, which may contribute to the attenuation of the formation of nitrotyrosine, an indication of nitrosative stress [26]. In this context, a combination of several active constituents of Hypericum species is the carrier of their anti-inflammatory activity.

[5-Lox_review_number_2-6] Wölfle U, Seelinger G, Schempp CM (fevereiro de 2014). «Topical application of St. John's wort (Hypericum perforatum)». Planta Med. 80 (2-3): 109–20. PMID 24214835. doi:10.1055/s-0033-1351019. Anti-inflammatory mechanisms of hyperforin have been described as inhibition of cyclooxygenase-1 (but not COX-2) and 5-lipoxygenase at low concentrations of 0.3 µmol/L and 1.2 µmol/L, respectively [52], and of PGE2 production in vitro [53] and in vivo with superior efficiency (ED50 = 1 mg/kg) compared to indomethacin (5 mg/kg) [54]. Hyperforin turned out to be a novel type of 5-lipoxygenase inhibitor with high effectivity in vivo [55] and suppressed oxidative bursts in polymorphonuclear cells at 1.8 µmol/L in vitro [56]. Inhibition of IFN-γ production, strong downregulation of CXCR3 expression on activated T cells, and downregulation of matrix metalloproteinase 9 expression caused Cabrelle et al. [57] to test the effectivity of hyperforin in a rat model of experimental allergic encephalomyelitis (EAE). Hyperforin attenuated the symptoms significantly, and the authors discussed hyperforin as a putative therapeutic molecule for the treatment of autoimmune inflammatory diseases sustained by Th1 cells.

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