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.
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 postinfection. 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. To 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 interferon-gamma (anti-IFN-gamma, 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-gamma, 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.
Berg-Candolfi
M
M
Department of Pharmacy, University of California San Francisco, CA, USA.
Candolfi
E
E
Benet
L Z
LZ
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D016572:Cyclosporine / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004917:Erythromycin / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology*; D007583:Jejunum / Q000187:drug effects / Q000201:enzymology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009573:Nitrites / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014124:Toxoplasmosis, Animal / Q000201:enzymology*
D000911:Antibodies, Monoclonal; D065607:Cytochrome P-450 Enzyme Inhibitors; D009573:Nitrites; C063904:N(G)-aminoarginine; D004917:Erythromycin; D007371:Interferon-gamma; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D001120:Arginine; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000111:Acetylcysteine