Suppression of intestinal and hepatic cytochrome P4503A in murine Toxoplasma infection. Effects of N-acetylcysteine and N^G-monomethyl-L-arginine on the hepatic suppression

Abstract

1. Cytochrome P4503A (CYP3A) expression was studied in a murine model of infection. Mice were infected with a cystogenic strain of Toxoplasma gondii and microsomes were prepared for liver homogenates and jejunum villus tip enterocytes on day 10 post-infection. Total cytochrome P450 (CYP) and CYP3A were quantitated, and CYP3A activity was determined.

2. In the infected mouse, total CYP and CYP3A contents fell in the liver (—39 and —49% respectively) and intestine (— 43 and —48% respectively), as did the rate of metabolism of erythromycin (Ery) and cyclosporine A (CyA), two markers of CYP3A activity (— 36 and —26% in the liver, —35 and —58% in the intestine).

3. éo determine the mechanism(s) involved in the depression of hepatic CYP3A, infected mice were treated on day 7·5 post-infection with a monoclonal antibody raised against interfron-γ (anti-IFN-γ), or from days 7·5 to 10 post-infection with either N^G — monomethyl-L-arginine (NMMA), an inhibitor of reactive nitrogen intermediates (RNI) production, or N-acetylcysteine (NAC), a reactive oxygen intermediates (ROI) scavenger.

4. Total CYP content was restored in the liver of infected mice treated with anti-IFN-γ, but with marked interindividual variability. NAC treatment led to a recovery in the liver of total CYP content (+ 35%), CYP3A content (total recovery), and the rates of Ery (+ 59%) and CyA (+ 87%) metabolism, whereas inconsistent results were obtained with NMMA. These results suggest that NAC, but probably not NMMA, partially protects hepatic CYP3A from Toxoplasma-mediated suppression in mouse.