In all organisms, the biotransformation of xenobiotics to less toxic and more hydrophilic compounds represents an effective defense strategy. In pathogens, the biotransformation of drugs (used for their elimination from the host) may provide undesirable protective effects that could potentially compromise the drug's efficacy. Accordingly, increased drug deactivation via accelerated biotransformation is now considered as one of the mechanisms of drug resistance. The present study summarizes the current knowledge regarding the biotransformation of anthelmintics, specifically drugs used to treat mainly nematodes, a group of parasites that are a significant health concern for humans and animals. The main biotransformation enzymes are introduced and their roles in anthelmintics metabolism in nematodes are discussed with a particular focus on their potential participation in drug resistance. Similarly, the inducibility of biotransformation enzymes with sublethal doses of anthelmintics is presented in view of its potential contribution to drug resistance development. In the conclusion, the main tasks awaiting scientists in this area are outlined.

• MeSH
• Anthelmintics * pharmacology   metabolism   pharmacokinetics   MeSH
• Biotransformation MeSH
• Nematoda * drug effects   metabolism   enzymology   MeSH
• Drug Resistance * MeSH
• Humans MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Anthelmintics * MeSH

Aldo-keto reductases (AKRs), a superfamily of NADP(H)-dependent oxidoreductases, catalyze the oxidoreduction of a wide variety of eobiotic and xenobiotic aldehydes and ketones. In mammals, AKRs play essential roles in hormone and xenobiotic metabolism, oxidative stress, and drug resistance, but little is known about these enzymes in the parasitic nematode Haemonchus contortus. In the present study, 22 AKR genes existing in the H. contortus genome were investigated and a phylogenetic analysis with comparison to AKRs in Caenorhabditis elegans, sheep and humans was conducted. The constitutive transcription levels of all AKRs were measured in eggs, larvae, and adults of H. contortus, and their expression was compared in a drug-sensitive strain (ISE) and a benzimidazole-resistant strain (IRE) previously derived from the sensitive strain by imposing benzimidazole selection pressure. In addition, the inducibility of AKRs by exposure of H. contortus adults to benzimidazole anthelmintic flubendazole in vitro was tested. Phylogenetic analysis demonstrated that the majority of AKR genes in H. contortus lack orthologues in the sheep genome, which is a favorable finding for considering AKRs as potential drug targets. Large differences in the expression levels of individual AKRs were observed, with AKR1, AKR3, AKR8, and AKR10 being the most highly expressed at most developmental stages. Significant changes in the expression of AKRs during the life cycle and pronounced sex differences were found. Comparing the IRE and ISE strains, three AKRs were upregulated, and seven AKRs were downregulated in adults. In addition, the expression of three AKRs was induced by flubendazole exposure in adults of the ISE strain. Based on these results, AKR1, AKR2, AKR3, AKR5, AKR10 and AKR19 in particular merit further investigation and functional characterization with respect to their potential involvement in drug biotransformation and anthelmintic resistance in H. contortus.

• Keywords
• AKR, Drug-resistance, Drug-susceptibility, Expression profile, Haemonchus contortus, Phylogenetic analysis,
• MeSH
• Aldehyde Reductase genetics   metabolism   MeSH
• Aldo-Keto Reductases * genetics   metabolism   MeSH
• Anthelmintics pharmacology   MeSH
• Benzimidazoles pharmacology   MeSH
• Caenorhabditis elegans genetics   drug effects   enzymology   MeSH
• Phylogeny * MeSH
• Haemonchus * genetics   drug effects   enzymology   MeSH
• Drug Resistance genetics   MeSH
• Humans MeSH
• Mebendazole * pharmacology   analogs & derivatives   MeSH
• Sheep MeSH
• Transcriptome MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Aldehyde Reductase MeSH
• Aldo-Keto Reductases * MeSH
• Anthelmintics MeSH
• Benzimidazoles MeSH
• flubendazole MeSH Browser
• Mebendazole * MeSH

Carbonyl-reducing enzymes (CREs) catalyse the reduction of carbonyl groups in many eobiotic and xenobiotic compounds in all organisms, including helminths. Previous studies have shown the important roles of CREs in the deactivation of several anthelmintic drugs (e.g., flubendazole and mebendazole) in adults infected with the parasitic nematode Haemonchus contortus, in which the activity of a CRE is increased in drug-resistant strains. The aim of the present study was to compare the abilities of nematodes of both a drug-susceptible strain (ISE) and a drug-resistant strain (IRE) to reduce the carbonyl group of flubendazole (FLU) in different developmental stages (eggs, L1/2 larvae, L3 larvae, and adults). In addition, the effects of selected CRE inhibitors (e.g., glycyrrhetinic acid, naringenin, silybin, luteolin, glyceraldehyde, and menadione) on the reduction of FLU were evaluated in vitro and ex vivo in H. contortus adults. The results showed that FLU was reduced by H. contortus in all developmental stages, with adult IRE females being the most metabolically active. Larvae (L1/2 and L3) and adult females of the IRE strain reduced FLU more effectively than those of the ISE strain. Data from the in vitro inhibition study (performed with cytosolic-like fractions of H. contortus adult homogenate) revealed that glycyrrhetinic acid, naringenin, mebendazole and menadione are effective inhibitors of FLU reduction. Ex vivo study data showed that menadione inhibited FLU reduction and also decreased the viability of H. contortus adults to a similar extent. Naringenin and mebendazole were not toxic at the concentrations tested, but they did not inhibit the reduction of FLU in adult worms ex vivo.

• Keywords
• Anthelmintics, Strongyloides, drug biotransformation, helminths, inhibitors,
• MeSH
• Anthelmintics * pharmacology   therapeutic use   MeSH
• Haemonchus * MeSH
• Glycyrrhetinic Acid * pharmacology   MeSH
• Larva MeSH
• Mebendazole pharmacology   therapeutic use   MeSH
• Vitamin K 3 pharmacology   MeSH
• Animals MeSH
• Check Tag
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anthelmintics * MeSH
• flubendazole MeSH Browser
• Glycyrrhetinic Acid * MeSH
• Mebendazole MeSH
• Vitamin K 3 MeSH

Albendazole (ABZ) is an anthelmintic frequently used to treat haemonchosis, a common parasitosis of ruminants caused by the gastrointestinal nematode Haemonchus contortus. This parasite is able to protect itself against ABZ via the formation of inactive ABZ-glycosides. The present study was designed to deepen the knowledge about the role of UDP-glycosyltransferases (UGTs) in ABZ glycosylation in H. contortus. The induction effect of phenobarbital, a classical inducer of UGTs, as well as ABZ and ABZ-sulphoxide (ABZSO, the main active metabolite of ABZ) on UGTs expression and UGT activity toward ABZ was studied ex vivo in isolated adult nematodes. The effect of three potential UGT inhibitors (5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine and sulfinpyrazone) on ABZ glycosylation was tested. Pre-incubation of nematodes with ABZ and ABZSO led to increased expression of several UGTs as well as ABZ-glycosides formation in subsequent treatment. Phenobarbital also induced UGTs expression, but did not affect ABZ biotransformation. In the nematode's subcellular fraction, sulfinpyrazone inhibited UGT activity toward ABZ, although no effect of other inhibitors was observed. The inhibitory potential of sulfinpyrazone on the formation of ABZ-glycosides was also proved ex vivo in living nematodes. The obtained results confirmed the role of UGTs in ABZ biotransformation in H. contortus adults and revealed sulfinpyrazone as a potent inhibitor of ABZ glycosylation in this parasite. The possible use of sulfinpyrazone with ABZ in combination therapy merits further research.

• Keywords
• Anthelmintic resistance, Anthelmintics biotransformation, Benzimidazoles, Detoxification, Gene expression, Glycosylated metabolites, Glycosylation, Nematodes, UGT inhibitors, UHPLC-MS/MS,
• MeSH
• Albendazole MeSH
• Anthelmintics * therapeutic use   MeSH
• Phenobarbital metabolism   pharmacology   therapeutic use   MeSH
• Glycosides metabolism   pharmacology   therapeutic use   MeSH
• Glycosyltransferases MeSH
• Haemonchus * MeSH
• Nematoda * MeSH
• Sheep Diseases * drug therapy   MeSH
• Sheep MeSH
• Sulfinpyrazone metabolism   pharmacology   therapeutic use   MeSH
• Uridine Diphosphate MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Albendazole MeSH
• Anthelmintics * MeSH
• Phenobarbital MeSH
• Glycosides MeSH
• Glycosyltransferases MeSH
• Sulfinpyrazone MeSH
• Uridine Diphosphate MeSH

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.

• Keywords
• ABC-transporters, P-glycoprotein, UDP-glycosyl transferases, anthelmintics, benzimidazoles, cytochromes P450, drug resistance, nematode,
• MeSH
• Albendazole analogs & derivatives   pharmacology   MeSH
• Antinematodal Agents pharmacology   MeSH
• Haemonchus drug effects   enzymology   MeSH
• Drug Resistance * MeSH
• Inactivation, Metabolic MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Albendazole MeSH
• albendazole sulfoxide MeSH Browser
• Antinematodal Agents MeSH

Haemonchus contortus (family Trichostrongylidae, Nematoda), a hematophagous gastrointestinal parasite found in small ruminants, has a great ability to develop resistance to anthelmintic drugs. We studied the biotransformation of the three benzimidazole anthelmintics: albendazole (ABZ), ricobendazole (albendazole S-oxide; RCB) and flubendazole (FLU) in females and males of H. contortus in both a susceptible ISE strain and resistant IRE strain. The ex vivo cultivation of living nematodes in culture medium with or without the anthelmintics was used. Ultrasensitive UHPLC/MS/MS analysis revealed 9, 7 and 12 metabolites of ABZ, RCB and FLU, respectively, with most of these metabolites now described in the present study for the first time in H. contortus. The structure of certain metabolites shows the presence of biotransformation reactions not previously reported in nematodes. There were significant qualitative and semi-quantitative differences in the metabolites formed by male and female worms. In most cases, females metabolized drugs more extensively than males. Adults of the IRE strain were able to form many more metabolites of all the drugs than adults of the ISE strain. Some metabolites were even found only in adults of the IRE strain. These findings suggest that increased drug metabolism may play a role in resistance to benzimidazole drugs in H. contortus.

• Keywords
• Anthelmintics, Benzimidazole, Drug metabolism, Drug resistance, Nematode,
• MeSH
• Albendazole analogs & derivatives   metabolism   pharmacology   MeSH
• Anthelmintics metabolism   pharmacology   MeSH
• Biochemical Phenomena MeSH
• Biotransformation MeSH
• Haemonchus metabolism   MeSH
• Haemonchiasis drug therapy   parasitology   veterinary   MeSH
• Drug Resistance * MeSH
• Mebendazole analogs & derivatives   metabolism   pharmacology   MeSH
• Sheep Diseases drug therapy   parasitology   MeSH
• Sheep parasitology   MeSH
• Sex Factors MeSH
• Tandem Mass Spectrometry MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Albendazole MeSH
• albendazole sulfoxide MeSH Browser
• Anthelmintics MeSH
• flubendazole MeSH Browser
• Mebendazole MeSH