Abstract
BackgroundThe mechanisms by which malaria up and down-regulates CYP activities are not understood yet. It is also unclear whether CYP activities are modulated during non-lethal malaria infections. This study was undertaken to evaluate the time course of CYP alterations in lethal (Plasmodium berghei ANKA) and non-lethal (Plasmodium chabaudi chabaudi) murine malaria. Additionally, hypotheses on the association of CYP depression with enhanced nitric oxide (NO) production, and of CYP2a5 induction with endoplasmic reticulum dysfunction, enhanced haem metabolism and oxidative stress were examined as well.MethodsFemale DBA-2 and C57BL/6 mice were infected with P.berghei ANKA or P. chabaudi and killed at different post-infection days. Infection was monitored by parasitaemia rates and clinical signs. NO levels were measured in the serum. Activities of CYP1a (ethoxyresorufin-O-deethylase), 2b (benzyloxyresorufin-O-debenzylase), 2a5 (coumarin-7-hydroxylase) and uridine-diphosphoglucuronyl-transferase (UGT) were determined in liver microsomes. Glutathione-S-transferase (GST) activity and concentrations of gluthatione (GSH) and thiobarbituric acid-reactive substances (TBARS) were determined in the liver. Levels of glucose-regulated protein 78 (GRP78) were evaluated by immunoblotting, while mRNAs of haemoxygenase-1 (HO-1) and inducible nitric oxide synthase (iNOS) were determined by quantitative RT-PCR.ResultsPlasmodium berghei depressed CYP1a and 2b and induced 2a5 in DBA-2 mice. In P.berghei-infected C57BL/6 mice CYP activities remained unaltered. In both strains, GST and UGT were not affected by P.berghei. Plasmodium c. chabaudi depressed CYP1a and 2b and induced 2a5 activities on the day of peak parasitaemia or near this day. CYP2a5 induction was associated with over-expression of HO-1 and enhanced oxidative stress, but it was not associated with GRP78 induction, a marker of endoplasmic reticulum stress. Plasmodium chabaudi increased serum NO on days near the parasitaemia peak in both strains. Although not elevating serum NO, P.berghei enhanced iNOS mRNA expression in the liver.ConclusionDown-regulation of CYP1a and 2b and induction of 2a5 occurred in lethal and non-lethal infections when parasitaemia rates were high. A contribution of NO for depression of CYP2b cannot be ruled out. Results were consistent with the view that CYP2a5 and HO-1 are concurrently up-regulated and suggested that CYP2a5 induction may occur in the absence of enhanced endoplasmic reticulum stress.
Highlights
The mechanisms by which malaria up and down-regulates cytochrome P450 enzymes (CYP) activities are not understood yet
Data from this study showed that levels of thiobarbituric acid-reactive substances (TBARS) - a marker for lipid peroxidation and oxidative stress - were enhanced in the liver of DBA-2 mice infected with P.berghei, thereby supporting the view that hepatic tissue is under oxidative stress during severe malaria infection
In conclusion, results from this study showed that down-regulation of CYP1a and 2b, as well as up-regulation of CYP2a5 occur in both lethal and non-lethal murine malaria
Summary
The mechanisms by which malaria up and down-regulates CYP activities are not understood yet. Several studies have shown that stimulation of host defense mechanisms against infections, as well as treatment with pro-inflammatory cytokines, modulate the expression and activity of cytochrome P450 enzymes (CYP), thereby modifying the kinetics of drugs and toxicants [1,2]. Along this line, it was reported that Plasmodium berghei infection depressed the total content of cytochrome P450s (CYPs) and the expression and activity of several CYP isoforms in the rodent liver [3,4,5,6]. In human as well as in rodent cells, free haem excess up-regulates the expression of HO-1, the rate limiting enzyme in the process of converting potentially toxic free haem into equimolar amounts of carbon monoxide (CO), biliverdin and iron (Fe) [14,15]
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