Effects of Plasmodium berghei infection on cytochromes P-450 2E1 and 3A2

Metabolism and disposition of most drugs used to treat malaria are substant ially altered in malaria infection. Few data are available that specify eff ects of malaria infection on drug metabolism pathways in humans or animal m odel systems. In this report, studies were undertaken to determine the effe ct of Plasmodium berghei infection on cytochrome P-450 (CYP450) 2E1 and 3A2 -mediated metabolism and enzyme expression in rat liver microsomes. Malaria infection (MAL) resulted in significant decreases in total cytochrome P-45 0 content (56%, P <0.05) and NADPH cytochrome P-450 reductase activity (32% , P <0.05) as compared to control (CON) rats. Chlorzoxazone 4-hydroxylase a ctivity (CYP2E1-mediated) showed no significant difference between CON and MAL microsomes while testosterone 6-beta-hydroxylase activity (CYP3A2-media ted) was reduced by 41% (P <0.05) in MAL. Enzyme kinetic studies and immuno blot analysis indicate that the loss of activity for CYP3A2 in malaria infe ction is due to significantly decreased CYP3A2 protein expression. The alte red expression of CYP450s in malaria infection should be taken into account when treating patients with malaria in order to minimize drug-drug interac tions or toxicity.