Xenobiotic metabolizing enzymes and metabolism of anthelminthics in helminths

Abstract

Anthelminthics remain the only accessible means in the struggle against helminth parasites, which cause significant morbidity and mortality in man and farm animals. The treatment of helminthic infections has become problematic because of frequent drug resistance of helminth parasites. The development of drug resistance can be facilitated by the action of xenobiotic metabolizing enzymes (XMEs). In all organisms, XMEs serve as an efficient defense against the potential negative action of xenobiotics. The activities of XMEs determine both desired and undesired effects of drugs, and the knowledge of drug metabolism is necessary for safe, effective pharmacotherapy. While human and mammalian XMEs have been intensively studied for many years, XMEs of helminth parasites have undergone relatively little investigation, so far. However, many types of XMEs, including oxidases, reductases, hydrolases, transferases, and transporters, have been described in several helminth species. XMEs of helminth parasites may protect these organisms from the toxic effects of anthelminthics. In case of certain anthelminthics, metabolic deactivation was reported in helminth larvae and/or adults. Moreover, if a helminth is in the repeated contact with an anthelminthic, it defends itself against the chemical stress by the induction of biotransformation enzymes or transporters. This induction can represent an advantageous defense strategy of the parasites and may facilitate the drug-resistance development.

Biotransformation of anthelmintics and the activity of drug-metabolizing enzymes in the tapeworm Moniezia expansa

“…The presence of reductive drug metabolism in M. expansa was proven by results from ex vivo cultivations, where the less potent FLU and MBZ metabolites with reduced carbonyl group were found (Dayan, 2003;Ceballos et al 2011). These metabolites were previously identified in other helminths species: Haemonchus contortus, Hymenolepis diminuta and Dicrocoelium dendriticum (Cvilink et al 2009a). From in vitro experiments it can be seen that the formation of reduced metabolites took place in cytosollike fraction of M. expansa.…”

Unique structure and regulation of the nematode detoxification gene regulator, SKN-1: implications to understanding and controlling drug resistance

“…Despite the fundamental and conserved role of xenobiotic detoxification in drug resistance, these processes are poorly understood in nematodes. The limited knowledge of these processes in helminths has been reviewed in detail recently (Cvilink et al 2009) and we only summarize it here briefly.…”

“…In animal cells, xenobiotic detoxification is modeled as occurring in three sequential and interdependent phases. In phase I, enzymes such as cytochrome P450s, short-chain dehydrogenases, and reductases uncover or insert reactive and hydrophilic groups onto xenobiotics leaving them more accessible for further processing (Iyanagi 2007; Cvilink et al 2009). The genome of Caenorhabditis elegans, the free-living genetic model nematode, is predicted to contain 86 cytochrome P450s and 68 short-chain dehydrogenases (Lindblom and Dodd 2006; the genome of Pristionchus pacificus , a beetle-associated nematode, is predicted to contain 198 cytochrome P450s (Dieterich et al 2008).…”

Inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica

“…In sheep, it has been shown that this biotransformation is carried out by the flavin monooxygenase (FMO) and cytochrome P450 (CYP 450) enzyme systems (Virkel et al 2006). The metabolism transforms the drug into more polar metabolites that are excreted more easily (Cvilink et al 2009). F. hepatica has also been shown to have the ability to metabolise TCBZ (Mottier et al 2004;Robinson et al 2004).…”