Abstract
The basic metabolic cytochrome P450 (CYP) system is essential for biotransformation of sterols and xenobiotics including drugs, for synthesis and degradation of signaling molecules in all living organisms. Most eukaryotes including free-living flatworms have numerous paralogues of the CYP gene encoding heme monooxygenases with specific substrate range. Notably, by contrast, the parasitic flatworms have only one CYP gene. The role of this enzyme in the physiology and biochemistry of helminths is not known. The flukes and tapeworms are the etiologic agents of major neglected tropical diseases of humanity. Three helminth infections (Opisthorchis viverrini, Clonorchis sinensis and Schistosoma haematobium) are considered by the International Agency for Research on Cancer (IARC) as definite causes of cancer. We focused our research on the human liver fluke Opisthorchis felineus, an emerging source of biliary tract disease including bile duct cancer in Russia and central Europe. The aims of this study were (i) to determine the significance of the CYP activity for the morphology and survival of the liver fluke, (ii) to assess CYP ability to metabolize xenobiotics, and (iii) to localize the CYP activity in O. felineus tissues. We observed high constitutive expression of CYP mRNA (Real-time PCR) in O. felineus. This enzyme metabolized xenobiotics selective for mammalian CYP2E1, CYP2B, CYP3A, but not CYP1A, as determined by liquid chromatography and imaging analyses. Tissue localization studies revealed the CYP activity in excretory channels, while suppression of CYP mRNA by RNA interference was accompanied by morphological changes of the excretory system and increased mortality rates of the worms. These results suggest that the CYP function is linked to worm metabolism and detoxification. The findings also suggest that the CYP enzyme is involved in vitally important processes in the organism of parasites and is a potential drug target.
Highlights
The heme-containing enzymes cytochromes P450 (CYPs) are widely distributed in living organisms from bacteria to mammals [reviewed in Refs. 1, 2–3]
cytochrome P450 (CYP) enzymes act as components of a monooxygenase system; they display biological functions ranging from detoxification of environmental pollutants to synthesis and degradation of endogenous signaling molecules [1]
In the free-living nematode Caenorhabditis elegans, one of the CYP enzymes participates in the synthesis of a steroid hormone necessary for worm development [3], whereas the other CYP enzyme is involved in fatty acids homeostasis [4]
Summary
The heme-containing enzymes cytochromes P450 (CYPs) are widely distributed in living organisms from bacteria to mammals [reviewed in Refs. 1, 2–3]. More than 80% of existing prescription drugs undergo the unavoidable step of biotransformation mediated by cytochromes Р450 This step typically limits the speed of the biotransformation process and of excretion of the drugs [1]. Given these roles, CYP are functionally important for survival of invading pathogens. Parasites with one allele of CYP show impaired growth, lower membrane potential, reduced virulence, and higher sensitivity to drugs [2]. Inactivation of both copies of a CYP gene is lethal for this microbe [2]. It is known that in fungi, the CYP system is an important pharmacological target because it participates in the synthesis of the cell wall of spores, in the metabolism of membrane sterols, and in production of metabolites with antibacterial properties [1]
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