Flow cytometry analysis of drug transport mechanisms in Haemonchus contortus susceptible or resistant to anthelmintics

Kerbœuf, Dominique; Chambrier, Pierre; Vern, Yves Le; Aycardi, J.

doi:10.1007/s004360050519

Cited by 40 publications

(40 citation statements)

References 17 publications

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“…A similar stepwise selection of BZ resistance also occurs in some Trichostrongylus colubriformis and Ostertagia circumcincta populations (45,68). Furthermore, Kerboeuf et al (84) recently provided indirect evidence that P-glycoproteins (P-gp) also play a role in BZ resistance in H. contortus. P-gp are involved in multidrug resistance in mammalian tumor cells, Leishmania, and Plasmodium and in resistance to toxic compounds in C. elegans.…”

Section: Mechanisms Of Drug Resistancementioning

confidence: 91%

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Drug Resistance in Human Helminths: Current Situation and Lessons from Livestock

Geerts

Gryseels

2000

Clinical Microbiology Reviews

231

130

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Section: Mechanisms Of Drug Resistancementioning

confidence: 91%

“…Since it has been shown that P-gp plays a role in resistance to BZ and IVM in H. contortus (12,84,158), it can be expected that the same resistance mechanism might develop in many other helminths, including O. volvulus.…”

Section: Detection Of Drug Resistancementioning

confidence: 99%

Drug Resistance in Human Helminths: Current Situation and Lessons from Livestock

Geerts

Gryseels

2000

Clinical Microbiology Reviews

231

130

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“…When MXR inhibitors were used, an in crease of the fluorescence was noted, as previously re ported for other species (Cornwall et al 1995, Kerboeuf et al 1999, Hamdoun et al 2004, Marin et al 2004, Zaja et al 2006). …”

Section: Rb Incorporationmentioning

confidence: 63%

“…This indirect measurement method has been used for a long time and is still used for the detection of Pgplike and MRP-like activities (Neyfakh 1988, Kerboeuf et al 1999, Hamdoun et al 2004, Lüders et al 2009), as well as for the detection of MXR/MDR activity (Holland Toomey & Epel 1993, Cornwall et al 1995, Zaja et al 2006, Caminada et al 2008. The CsA and Ver are not as specific as first claimed 10 yr ago.…”

Section: Response Comparisonmentioning

confidence: 99%

Multixenobiotic resistance in coelomocytes from three echinoderm species

Doussantousse¹,

Pelletier²,

Beaulieu³

et al. 2011

Aquat. Biol.

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Multixenobiotic resistance (MXR) proteins are known to be present in most living organisms, but only a few studies have been conducted on echinoderms and especially on their circulating cells, the coelomocytes. The objective of the present study was to investigate the presence of MXR activity in coelomocytes of the sea urchin Strongylocentrotus droebachiensis, the sea star Leptasterias polaris and the sea cucumber Cucumaria frondosa. Cells were exposed to fluorescent substrates (1 µM Rhodamine B [RB] The combination RB + MK induced a fluorescence increase in S. droebachiensis and C. frondosa coelomocytes. Finally, the combination CAM + MK induced a fluorescence diminution in L. polaris coelomocytes and S. droebachiensis vibratile cells. This difference in fluorescence incorporation indicated an MXR-like activity in coelomocytes, probably due to the presence of a P-glycoprotein (Pgp) and a multidrug resistance-associated protein (MRP)-like transporter. Western blot analysis was also carried out (Ab C219 and Ab C9) in order to detect potential MXR proteins using anti-MXR antibodies. Both Pgp and MRP were detected, but could not be further discriminated. MXR activity was clearly demonstrated in coelomocytes of S. droebachiensis, L. polaris and C. frondosa, although the identity of proteins responsible for this activity needs to be confirmed. KEY WORDS: Multixenobiotic resistance · MXR · Echinoderms · Coelomocytes · P-glycoprotein · Pgp · Multidrug resistance-associated proteins · MRPsResale or republication not permitted without written consent of the publisher Aquat Biol 12: 81-96, 2011 Pgp is known to be the primary active transporter of unmodified xenobiotics (Zaja et al. 2007), transporting mostly large and moderately hydrophobic cations (Litman et al. 2001). It is widely distributed in tissues and has a variety of physiological roles in healthy cells, such as lipid transport, intracellular cholesterol trafficking and the cytotoxic activity of NK and T cells (Johnstone et al. 2000). Among the family of MRPs, MRP1 facilitates the extrusion of numerous glutathione, glucuronate and sulphate conjugates. MRP1 is a ubiquitous protein taking part in various physiological functions including defence against xenobiotics and endogenous toxic metabolites, leukotrienemediated inflammatory responses, as well as protection from the toxic effect of oxidative stress (Bakos & Homolya 2007).A combination of substrates and inhibitors is often used to indicate MXR activity (Neyfakh 1988, Cornwall et al. 1995, Marin et al. 2004). Since some substrates and inhibitors are more specific to one MXR protein than to another, it is sometimes possible to discriminate the proteins involved. For example, Rhodamine B (RB) is often used as a Pgp substrate (Minier & Moore 1996, Reungpatthanaphong et al. 2003, Zaja et al. 2006) and a similar molecule, Rhodamine 123, is used as a Pgp-and MRP-like substrate (Hollo et al. 1996, Daoud et al. 2000. Calcein-AM (CAM) is also known as a substrate for both Pgp-like and MRP-like proteins,...

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“…Active Pgp was later detected in the gastrointestinal nematode Haemonchus contortus (31) by use of UIC2 monoclonal antibody (MAb), which specifically binds the active form of the protein (40). The role of Pgp in xenobiotic transport has also been demonstrated in this nematode by use of rhodamine 123 (R123) (29) as a specific Pgp substrate (44).…”

mentioning

confidence: 99%

Anthelmintics Are Substrates and Activators of Nematode P Glycoprotein

Kerbœuf

Guégnard

2011

Antimicrob Agents Chemother

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P glycoproteins (Pgp), members of the ABC transporter superfamily, play a major role in chemoresistance. In nematodes, Pgp are responsible for resistance to anthelmintics, suggesting that they are Pgp substrates, as they are in mammalian cells. However, their binding to nematode Pgp and the functional consequences of this interaction have not been investigated. Our study showed that levamisole and most of the macrocyclic lactones (MLs) are Pgp substrates in nematodes. Ivermectin, although a very good substrate in mammalian cells, is poorly transported. In contrast to their inhibitory effect on mammalian Pgp, these drugs had a stimulatory effect on the transport activity of the reference Pgp substrate rhodamine 123 (R123) in the nematode. This may be due to a specific sequence of nematode Pgp, which shares only 44% identity with mammalian Pgp. Other factors, such as the affinity of anthelmintics for Pgp and their concentration in the Pgp microenvironment, could also differ in nematodes, as suggested by the specific relationship observed between the octanol-water partition coefficient (log P) of MLs and R123 efflux. Nevertheless, some similarities were also observed in the functional activities of the mammalian and nematode Pgp. As in mammalian cells, substrates known to bind the H site (Hoechst 33342 and colchicine) activated the R site, resulting in an increased R123 efflux. Our findings thus show that ML anthelmintics, which inhibit Pgp-mediated efflux in mammals, activate transport activity in nematodes and suggest that several substituents in the ML structure are involved in modulating the stimulatory effect.

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Flow cytometry analysis of drug transport mechanisms in Haemonchus contortus susceptible or resistant to anthelmintics

Cited by 40 publications

References 17 publications

Drug Resistance in Human Helminths: Current Situation and Lessons from Livestock

Drug Resistance in Human Helminths: Current Situation and Lessons from Livestock

Multixenobiotic resistance in coelomocytes from three echinoderm species

Anthelmintics Are Substrates and Activators of Nematode P Glycoprotein

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