The efficacy of anthelmintic therapy of farm animals rapidly decreases due to drug resistance development in helminths. In resistant isolates, the increased expression and activity of drug-metabolizing enzymes (DMEs), e.g. cytochromes P450 (CYPs), UDP-glycosyltransferases (UGTs) and P-glycoprotein transporters (P-gps), in comparison to sensitive isolates have been described. However, the mechanisms and circumstances of DMEs induction are not well known. Therefore, the present study was designed to find the changes in expression of CYPs, UGTs and P-gps in adult parasitic nematodes Haemonchus contortus exposed to sub-lethal doses of the benzimidazole anthelmintic drug albendazole (ABZ) and its active metabolite ABZ-sulfoxide (ABZSO). In addition, the effect of ABZ at sub-lethal doses on the ability to deactivate ABZ during consequent treatment was studied. The results showed that contact of H. contortus adults with sub-lethal doses of ABZ and ABZSO led to a significant induction of several DMEs, particularly cyp-2, cyp-3, cyp-6, cyp-7, cyp-8, UGT10B1, UGT24C1, UGT26A2, UGT365A1, UGT366C1, UGT368B2, UGT367A1, UGT371A1, UGT372A1 and pgp-3, pgp-9.1, pgp-9.2, pgp-10. This induction led to increased formation of ABZ metabolites (especially glycosides) and their increased export from the helminths' body into the medium. The present study demonstrates for the first time that contact of H. contortus with sub-lethal doses of ABZ (e.g. during underdose treatment) improves the ability of H. contortus adults to deactivate ABZ in consequent therapy.

Department of Biochemical Sciences Faculty of Pharmacy Charles University Heyrovského 1203 500 05 Hradec Králové Czech Republic

Department of Pharmacology and Toxicology Faculty of Pharmacy Charles University Heyrovského 1203 Hradec Králové Czech Republic

000      

00000naa a2200000 a 4500

001      

bmc21012348

003      

CZ-PrNML

005      

20221024092656.0

007      

ta

008      

210420s2020 xxk f 000 0|eng||

009      

AR

024    7_

$a 10.1186/s13567-020-00820-x $2 doi

035    __

$a (PubMed)32703268

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a xxk

100    1_

$a Kellerová, Pavlína $u Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic

245    10

$a Sub-lethal doses of albendazole induce drug metabolizing enzymes and increase albendazole deactivation in Haemonchus contortus adults / $c P. Kellerová, L. Raisová Stuchlíková, P. Matoušková, K. Štěrbová, J. Lamka, M. Navrátilová, I. Vokřál, B. Szotáková, L. Skálová

520    9_

$a The efficacy of anthelmintic therapy of farm animals rapidly decreases due to drug resistance development in helminths. In resistant isolates, the increased expression and activity of drug-metabolizing enzymes (DMEs), e.g. cytochromes P450 (CYPs), UDP-glycosyltransferases (UGTs) and P-glycoprotein transporters (P-gps), in comparison to sensitive isolates have been described. However, the mechanisms and circumstances of DMEs induction are not well known. Therefore, the present study was designed to find the changes in expression of CYPs, UGTs and P-gps in adult parasitic nematodes Haemonchus contortus exposed to sub-lethal doses of the benzimidazole anthelmintic drug albendazole (ABZ) and its active metabolite ABZ-sulfoxide (ABZSO). In addition, the effect of ABZ at sub-lethal doses on the ability to deactivate ABZ during consequent treatment was studied. The results showed that contact of H. contortus adults with sub-lethal doses of ABZ and ABZSO led to a significant induction of several DMEs, particularly cyp-2, cyp-3, cyp-6, cyp-7, cyp-8, UGT10B1, UGT24C1, UGT26A2, UGT365A1, UGT366C1, UGT368B2, UGT367A1, UGT371A1, UGT372A1 and pgp-3, pgp-9.1, pgp-9.2, pgp-10. This induction led to increased formation of ABZ metabolites (especially glycosides) and their increased export from the helminths' body into the medium. The present study demonstrates for the first time that contact of H. contortus with sub-lethal doses of ABZ (e.g. during underdose treatment) improves the ability of H. contortus adults to deactivate ABZ in consequent therapy.

650    _2

$a albendazol $x analogy a deriváty $x farmakologie $7 D015766

650    _2

$a zvířata $7 D000818

650    _2

$a antinematodní látky $x farmakologie $7 D000969

650    _2

$a vztah mezi dávkou a účinkem léčiva $7 D004305

650    12

$a léková rezistence $7 D004351

650    _2

$a Haemonchus $x účinky léků $x enzymologie $7 D006189

650    _2

$a metabolická inaktivace $7 D008658

655    _2

$a časopisecké články $7 D016428

700    1_

$a Raisová Stuchlíková, Lucie $u Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic $7 xx0277923

700    1_

$a Matoušková, Petra $u Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic

700    1_

$a Štěrbová, Karolína, $u Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic $d 1995- $7 xx0277541

700    1_

$a Lamka, Jiří $u Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovského 1203, Hradec Králové, Czech Republic

700    1_

$a Navrátilová, Martina $u Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic

700    1_

$a Vokřál, Ivan $u Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovského 1203, Hradec Králové, Czech Republic

700    1_

$a Szotáková, Barbora $u Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic

700    1_

$a Skálová, Lenka $u Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic. lenka.skalova@faf.cuni.cz

773    0_

$w MED00177074 $t Veterinary research $x 1297-9716 $g Roč. 51, č. 1 (2020), s. 94

856    41

$u https://pubmed.ncbi.nlm.nih.gov/32703268 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y p $z 0

990    __

$a 20210420 $b ABA008

991    __

$a 20221024092654 $b ABA008

999    __

$a ok $b bmc $g 1650673 $s 1132727

BAS    __

$a 3

BAS    __

$a PreBMC

BMC    __

$a 2020 $b 51 $c 1 $d 94 $e 20200723 $i 1297-9716 $m Veterinary research $n Vet Res $x MED00177074

GRA    __

$a 18-07724S $p Grantová Agentura České Republiky

GRA    __

$a PRIMUS/17/SCI/4 $p Univerzita Karlova v Praze

GRA    __

$a UNCE/18/SCI/012 $p Univerzita Karlova v Praze

GRA    __

$a SVV 260 550 $p Univerzita Karlova v Praze

GRA    __

$a EFSA-CDN [CZ.02.1.01/0.0/0.0/16_019/0000841] $p Ministerstvo Školství, Mládeže a Tělovýchovy

LZP    __

$a Pubmed-20210420