Abstract
The basic metabolic cytochrome P450 (CYP) proteins are essential for the biotransformation of sterols and xenobiotics. By contrast, the Toxoplasma gondii genome contains only one CYP gene, and the role of this enzyme in the physiology and biochemistry of apicomplexan parasites is unknown. Because it is a potential resistance gene, identifying the functionality of P450 in T. gondii is particularly important. Knocking out Tg-P450 had no significant effect on T. gondii survival, but mice infected with parasites overexpressing Tg-P450 exhibited significantly enhanced pathogenicity. Enzyme activity analyses demonstrated that this protein has mammalian CYP2B and CYP3A enzymatic activity. In addition, T. gondii lacking the P450 gene exhibited reduced resistance to quinine, mefloquine and clarithromycin compared with parasites overexpressing Tg-P450. These results suggest that P450 functions in T. gondii metabolism and detoxification is involved in vitally important processes in parasitic organisms, making this enzyme a potential drug target.
Highlights
T. gondii is a globally ubiquitous pathogen that infects approximately 30% of the world population
Elucidating the functions of Tg-P450 in this study showed this protein is unnecessary for the survival of T. gondii tachyzoites, while P450 overexpression enhanced the pathogenicity of T. gondii in mice
Because these results were confusing, we evaluated whether Tg-P450 confers drug resistance like other organisms, revealing that it possesses CYP3A and CYP2B enzymatic activities but not CYP1A
Summary
T. gondii is a globally ubiquitous pathogen that infects approximately 30% of the world population. This obligate intracellular parasite is found in virtually all warm-blooded vertebrates, with feline species serving as the definitive host [1]. As a major opportunistic infection protozoan parasite, toxoplasmosis is usually reported in low-immunity populations, such as developing countries wherein HIV/AIDS is rampant, and it commonly causes focal brain lesions, coma and death [2]. T. gondii can resist the killing effects of many drugs that have previously proven to be effective against Plasmodium falciparum, an apicomplexan [3]. We hypothesize that some drug resistance genes exist in T. gondii that are associated with this phenomenon
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