Modulation of expression and activity of cytochrome P450s and alteration of praziquantel kinetics during murine schistosomiasis

Abstract

In this study, we investigated the expression and activity of liver cytochrome P450s (CYPs) and praziquantel (PZQ)

Hepatic Cytochrome P450s, Phase II Enzymes and Nuclear Receptors Are Downregulated in a Th2 Environment during Schistosoma mansoni Infection

“…However, there are discernible differences in the pattern of P450 expression depending on the disease and the type of immune response. Few studies have reported expression of P450 mRNAs or proteins during schistosomiasis (Sheweita et al, 2002;Gotardo et al, 2011), and almost nothing is known about phase II enzyme expression in this disease. Our data demonstrate that the granulomatous Th2 cytokine-dominated stage of S. mansoni infection is associated with a marked downregulation of most P450, Ugt, and Sult mRNAs studied, as well as Fmo3.…”

“…Much knowledge about the effects of schistosomiasis on P450-dependent drug metabolism has been gathered from studies on microsomal activities (Cha and Edwards, 1976;Cha et al, 1980a,b;Sheweita et al, 1998Sheweita et al, , 2002Manhães-Rocha et al, 2005;Conte et al, 2007;Gotardo et al, 2011). However, the contributions of mouse P450s to the metabolism of most drugs have not been rigorously established, and it is critical to know what happens to P450 gene products in this model.…”

“…The acute phase of human schistosomiasis is asymptomatic, whereas the chronic phase is more severe due to the inflammatory response to parasite eggs retained in the liver and intestines. The egg-laying period begins approximately 30 days after infection; as the infection continues, granulomas are formed at the sites of maximal accumulation of schistosome eggs in the liver, resulting in hepatosplenomegaly, hepatocellular fibrosis, and portal vein hypertension (Wilson et al, 2009;Gotardo et al, 2011). Given that schistosomiasis is prevalent in countries where coinfection for diseases such as HIV or malaria is common, it is important to ask how schistosomiasis affects the enzymes responsible for the metabolism of drugs given to treat not only schistosomiasis but also these coinfections.…”

“…Gotardo et al (2011) reported that hepatic Cyp1a2, Cyp2e1, and Cyp3a11 mRNAs were all downregulated in both male and female Swiss Webster mice at 55 days postinfection (dpi), but were downregulated at 30 dpi in female mice only. Even fewer data exist on phase II DME regulation during S. mansoni infection.…”

Activity of Praziquantel Enantiomers and Main Metabolites against Schistosoma mansoni

“…Albendazole is an inhibitor of CYP enzymes, and when it is administered concomitantly with PZQ, plasma R-PZQ levels are increased (16). The expression of CYP is also modulated during chronic schistosomiasis, with markedly lower activity in infected mice, probably resulting from the immune response to the infection (33). Interestingly, resistant isolates of S. mansoni do not inhibit host CYP as much as susceptible isolates do.…”