Up- and down-modulation of liver cytochrome P450 activities and associated events in two murine malaria models

• Published in: Malaria Journal
• Main Authors: Siqueira Carolina M, Gueiros Luciana S, Tavares Hellen S, Paixão Flavio HM, Carvalho Renato S, De-Oliveira Ana, Paumgartten Francisco JR
• Format: Article in Journal/Newspaper
• Language: English
• Published: BMC 2010
• Subjects: Arctic medicine. Tropical medicine; RC955-962; Infectious and parasitic diseases; RC109-216; Arctic
• Online Access: https://doi.org/10.1186/1475-2875-9-81; https://doaj.org/article/fa758554d2e1477ca41552c862353a8d

Abstract Background The 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. Methods Female 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. Results Plasmodium 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. ...