Effects of β-lapachone, a peroxide-generating quinone, on macromolecule synthesis and degradation in Trypanosoma cruzi

Goijman, Silvia G.; Stoppani, A. O. M.

doi:10.1016/0003-9861(85)90033-5

Cited by 61 publications

(32 citation statements)

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“…The generation of free radicals is concomitant with o-NQ reduction, suggesting that TcAKR participates in their metabolism (19,20,21). Trochine et al recently reported that TcAKR interacts with an immobilized derivative of Bz, suggesting that it also participates in the Bz mode of action (22).…”

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confidence: 99%

Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism

Garavaglia

Laverrière

Cannata

et al. 2016

Antimicrob Agents Chemother

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b Benznidazole (Bz), the drug used for treatment of Chagas' disease (caused by the protozoan Trypanosoma cruzi), is activated by a parasitic NADH-dependent type I nitroreductase (NTR I). However, several studies have shown that other enzymes are involved. The aim of this study was to evaluate whether the aldo-keto reductase from T. cruzi (TcAKR), a NADPH-dependent oxido-reductase previously described by our group, uses Bz as the substrate. We demonstrated that both recombinant and native TcAKR enzymes reduce Bz by using NADPH, but not NADH, as a cofactor. TcAKR-overexpressing epimastigotes showed higher NADPH-dependent Bz reductase activity and a 50% inhibitory concentration (IC 50 ) value for Bz 1.8-fold higher than that of the controls, suggesting that TcAKR is involved in Bz detoxification instead of activation. To understand the role of TcAKR in Bz metabolism, we studied TcAKR expression and NADPH/NADH-dependent Bz reductase activities in two T. cruzi strains with differential susceptibility to Bz: CL Brener and Nicaragua. Taking into account the results obtained with TcAKR-overexpressing epimastigotes, we expected the more resistant strain, Nicaragua, to have higher TcAKR levels than CL Brener. However, the results were the opposite. CL Brener showed 2-fold higher TcAKR expression and 5.7-fold higher NADPH-Bz reduction than the Nicaragua strain. In addition, NADH-dependent Bz reductase activity, characteristic of NTR I, was also higher in CL Brener than in Nicaragua. We conclude that although TcAKR uses Bz as the substrate, TcAKR activity is not a determinant of Bz resistance in wild-type strains and may be overcome by other enzymes involved in Bz activation, such as NADPH-and NADH-dependent reductases.C hagas' disease, caused by the protozoan Trypanosoma cruzi, affects 11 million people in Latin America (1). The parasite is usually transmitted to humans and other mammals by triatomine bugs. However, transmission can also be oral (through contaminated food), congenital, or transfusional or by organ transplantation, even in countries where the disease is not endemic (2). The course of infection includes an acute phase followed by an indeterminate phase without symptoms, which lasts throughout life in most infected people. Approximately 30% of patients can develop a chronic phase characterized by cardiac and/or digestive pathologies that can lead to death (3).Benznidazole (Bz) and, to a lesser extent, nifurtimox (Nx) are the drugs currently used for treatment of T. cruzi infection (4). Although the mechanism of action of these nitroheterocyclic compounds is not clearly understood, it is known that, to exert their trypanocidal effects, they need to be activated through the reduction of their nitro group (5). Several studies have proposed that an NADH-dependent trypanosomal type I nitroreductase (NTR I) is a key enzyme which catalyzes Bz and Nx activation in vivo (6,7,8,9). However, evidence indicates that although Bz is reduced to its anion radical, redox cycling may not be relevant for its mode of action, as ...

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confidence: 99%

Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism

Garavaglia

Laverrière

Cannata

et al. 2016

Antimicrob Agents Chemother

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“…10 Alkaloids are another important class of secondary metabolites having minimum one nitrogen atom either within the heterocyclic ring or outside the ring. Alkaloids are having wide range of physiological effects and pharmacological effects, including antibiotic, 11 antifungal, anti bacterial, anticancer, [12][13][14] narcotics, poisons, stimulants, 15 antimicrobial, anti-HIV and antiparasitic activities etc. 16 The other important metabolites present in plants are terpenoids, glycosides, lignin, coumarins, anthraquinones which also shows versatile therapeutic activity.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Analysis of Secondary Metabolites in Aqueous Extract of Clerodendrum Serratum

Tiwari¹,

Malairaman²,

Chanda³

2017

Int. Res. J. Pharm.

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The aim of this study was to quantify the secondary metabolites of aqueous extract of root of Clerodendrum serratum. The root of Clerodendrum serratum was extracted by using water. The yield of aqueous extract was 10%w/w. The total phenolic, flavonoid, saponin and alkaloidal content determined by spectrophotometric method. The amount of total phenolic in extracts was determined in comparison with the gallic acid, whereas total flavonoid, saponin, alkaloid content was estimated corresponding to rutin, diosgenin and atropine respectively. The phenolic, flavonoid, saponin and alkaloidal content of aqueous root extract of Clerodendrum serratum were found to be 134.4mg/g, 67.67mg/g, 38.2mg/g and 12.67mg/g respectively. The presence of such important metabolites in C. serratum indicates its therapeutic importance in man and animal.

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“…A large spectrum of therapeutic activities has been attributed to lapachol and many of its heterocyclic derivatives, such as prevention of cercarial skin penetration of Schistossoma mansoni (Pinto et al, 1977;Lima et al, 2002), trypanosomicidal (Austin, 1974;Goijman & Stoppani, 1985;Saúde-Guimarães & Faria, 2007), antiinfl ammatory (Almeida, 1990;Moon et al, 2007), antimicrobial (Antunes et al, 2006), antineoplastic; antimalarial activity (Carvalho et al, 1988) and against enteroviruses (Pinto et al, 1987;Subramanian & Ferreira, 1998;Teixeira et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Spasmolytic activity of lapachol and its derivatives, α and β-lapachone, on the guinea-pig ileum involves blockade of voltage-gated calcium channels

Cavalcante¹,

Silva²,

Carvalho³

et al. 2008

Rev. bras. farmacogn.

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Effects of β-lapachone, a peroxide-generating quinone, on macromolecule synthesis and degradation in Trypanosoma cruzi

Cited by 61 publications

References 25 publications

Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism

Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism

Quantitative Analysis of Secondary Metabolites in Aqueous Extract of Clerodendrum Serratum

Spasmolytic activity of lapachol and its derivatives, α and β-lapachone, on the guinea-pig ileum involves blockade of voltage-gated calcium channels

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