Increase of gluthatione S-transferase, carboxyl esterase and carbonyl reductase in Fasciola hepatica recovered from triclabendazole treated sheep

Scarcella, S.; Solana, María Victoria; Fernández, Vanesa; Lamenza, Pamela; Ceballos, Laura; Solana, H.

doi:10.1016/j.molbiopara.2013.09.002

Cited by 9 publications

(7 citation statements)

References 17 publications

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“…However, the low metabolic fate of this compound, observed even in sheep (Michiels et al, 1987), avoids any "protective" GST activity in susceptible F. hepatica. A similar GST activity increase has been reported previously (Scarcella et al, 2013) in the same adult F.…”

Section: Accepted Manuscriptsupporting

confidence: 91%

“…In fact, GST appears to be one of the major detoxification enzymes in parasitic helminths (Precious and Barrett, 1989). GSTs are essentially involved in the intracellular detoxification of numerous substances, including chemotherapeutic agents, and thus play a major role in the development of drug resistance (Cazenave et al, 1989;Hemingway et al, 2004;Scarcella et al, 2013). GSTs can also serve as non-enzymatic binding proteins involved in intracellular transport (Listowsky et al, 1988) and signalling processes (Cho et al, 2001).…”

Section: Closantelmentioning

confidence: 99%

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Understanding the main route of drug entry in adult Fasciola hepatica: Further insights into closantel pharmacological activity

Ceballos

Cantón

Cadenazzi

et al. 2017

Experimental Parasitology

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Closantel (CLS) is highly effective against adult liver flukes after its oral or subcutaneous (sc) administration in ruminants. Trans-tegumental diffusion and oral ingestion are the two potential routes available for the entry of drugs into Fasciola hepatica. The work reported here contributes to improve the understanding of CLS pharmacology. The main goals of were: I) to determine the pattern of in vivo CLS accumulation into adult F. hepatica and relevant tissues in CLS-treated sheep; II) to investigate the influence of the physicochemical composition of the incubation medium on the CLS diffusion process into adult F. hepatica; III) to assess the ovicidal activity of CLS against F. hepatica eggs; and IV) to investigate the in vivo effect of CLS treatment on glutathione S-transferases activity in adult liver flukes exposed to CLS. Fourteen healthy sheep were each orally infected with 75 F. hepatica metacercariae. Sixteen (16) weeks after infection, animals were treated with CLS by oral (n = 6, 10 mg/kg) or sub-cutaneous (sc) (n = 6, 5 mg/kg) route. At 12, 24 and 36 h post-treatment, animals were sacrificed (n = 2) and samples of blood, bile and adult F. hepatica were collected. In addition, flukes recovered from non-treated sheep (n = 2) were ex vivo incubated (60 min) in the presence of CLS in either RPMI or bile as incubation medium. CLS concentration was measured by HPLC. The ovicidal activity of CLS was investigated using eggs obtained from the bile of untreated sheep. Finally, glutathione S-transferase activity in F. hepatica recovered from untreated and CLS-treated sheep was assessed. In the in vivo studies, the highest CLS concentrations were measured in plasma and adult liver flukes. A positive correlation was observed between CLS concentration in plasma and in F. hepatica. Results obtained in the current work indicate that the in vivo accumulation of CLS into adult liver flukes occurs mainly by the oral route. After ex vivo incubation, the uptake of CLS by the parasite was markedly diminished in the presence of bile compared with that observed in the presence of RPMI as incubation medium. CLS lacks ovicidal activity at therapeutically relevant concentrations. Lastly, CLS significantly increased glutathione S-transferase activity in flukes recovered at 12 h (oral treatment) and 24 h (sc treatment), compared to the control liver flukes.

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Section: Accepted Manuscriptsupporting

confidence: 91%

Section: Closantelmentioning

confidence: 99%

Understanding the main route of drug entry in adult Fasciola hepatica: Further insights into closantel pharmacological activity

Ceballos

Cantón

Cadenazzi

et al. 2017

Experimental Parasitology

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“…Moreover, human carbonyl reductase 3 is induced during pro-inflammatory stimuli and acts as a sensor of oxidative stress 51 . In the trematode parasite F. hepatica , the causative agent of fasciolosis, two xenobiotic metabolizing enzymes (carbonyl reductase and GST) showed an increased activity after in vivo treatment with the anthelminthic drug triclabendazole, suggesting a detoxifying function for this enzyme 52 . In E. granulosus a high level of carbonyl reductase in PSCs exposed to H 2 O 2 might act to detoxify reactive carbonyl, preventing macromolecules damage.…”

Section: Discussionmentioning

confidence: 99%

Unraveling oxidative stress response in the cestode parasite Echinococcus granulosus

Cancela

Paes

Moura

et al. 2019

Sci Rep

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Cystic hydatid disease (CHD) is a worldwide neglected zoonotic disease caused by Echinococcus granulosus. The parasite is well adapted to its host by producing protective molecules that modulate host immune response. An unexplored issue associated with the parasite’s persistence in its host is how the organism can survive the oxidative stress resulting from parasite endogenous metabolism and host defenses. Here, we used hydrogen peroxide (H2O2) to induce oxidative stress in E. granulosus protoescoleces (PSCs) to identify molecular pathways and antioxidant responses during H2O2 exposure. Using proteomics, we identified 550 unique proteins; including 474 in H2O2-exposed PSCs (H-PSCs) samples and 515 in non-exposed PSCs (C-PSCs) samples. Larger amounts of antioxidant proteins, including GSTs and novel carbonyl detoxifying enzymes, such as aldo-keto reductase and carbonyl reductase, were detected after H2O2 exposure. Increased concentrations of caspase-3 and cathepsin-D proteases and components of the 26S proteasome were also detected in H-PSCs. Reduction of lamin-B and other caspase-substrate, such as filamin, in H-PSCs suggested that molecular events related to early apoptosis were also induced. We present data that describe proteins expressed in response to oxidative stress in a metazoan parasite, including novel antioxidant enzymes and targets with potential application to treatment and prevention of CHD.

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“…Previous studies have shown that when exposed to triclabendazole (TCBZ), there is a significant increase in the expression of carboxylesterase type B (CestB) in F. hepatica [18]. TCBZ is commonly used as an anthelmintic to treat fascioliasis in animals and humans, and the emergence of TCBZ-resistant strains in F. hepatica is primarily associated with its widespread use [2,7].…”

Section: Introductionmentioning

confidence: 99%

Single Amino Acid Polymorphisms in the Fasciola hepatica Carboxylesterase Type B Gene and Their Potential Role in Anthelmintic Resistance

Miranda-Miranda,

Cossío-Bayúgar,

Trejo-Castro

et al. 2023

Pathogens

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The expression of the Fasciola hepatica carboxylesterase type B (CestB) gene is known to be induced upon exposure to the anthelmintic triclabendazole (TCBZ), leading to a substantial rise in enzyme-specific activity. Furthermore, the nucleotide sequence of the CestB gene displays variations that can potentially result in radical amino acid substitutions at the ligand binding site. These substitutions hold the potential to impact both the ligand–protein interaction and the catalytic properties of the enzyme. Thus, the objective of our study was to identify novel CestB polymorphisms in TCBZ-resistant parasites and field isolates obtained from a highly endemic region in Central Mexico. Additionally, we aimed to assess these amino acid polymorphisms using 3D modeling against the metabolically oxidized form of the anthelmintic TCBZSOX. Our goal was to observe the formation of TCBZSOX-specific binding pockets that might provide insights into the role of CestB in the mechanism of anthelmintic resistance. We identified polymorphisms in TCBZ-resistant parasites that exhibited three radical amino acid substitutions at positions 147, 215, and 263. These substitutions resulted in the formation of a TCBZSOX-affinity pocket with the potential to bind the anthelmintic drug. Furthermore, our 3D modeling analysis revealed that these amino acid substitutions also influenced the configuration of the CestB catalytic site, leading to alterations in the enzyme’s interaction with chromogenic carboxylic ester substrates and potentially affecting its catalytic properties. However, it is important to note that the TCBZSOX-binding pocket, while significant for drug binding, was located separate from the enzyme’s catalytic site, rendering enzymatic hydrolysis of TCBZSOX impossible. Nonetheless, the observed increased affinity for the anthelmintic may provide an explanation for a drug sequestration type of anthelmintic resistance. These findings lay the groundwork for the future development of a molecular diagnostic tool to identify anthelmintic resistance in F. hepatica.

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Increase of gluthatione S-transferase, carboxyl esterase and carbonyl reductase in Fasciola hepatica recovered from triclabendazole treated sheep

Cited by 9 publications

References 17 publications

Understanding the main route of drug entry in adult Fasciola hepatica: Further insights into closantel pharmacological activity

Understanding the main route of drug entry in adult Fasciola hepatica: Further insights into closantel pharmacological activity

Unraveling oxidative stress response in the cestode parasite Echinococcus granulosus

Single Amino Acid Polymorphisms in the Fasciola hepatica Carboxylesterase Type B Gene and Their Potential Role in Anthelmintic Resistance

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