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