Mechanism of hepatic cytochrome P450 modulation during Listeria monocytogenes infection in mice.
There have been numerous reports of altered drug clearance during episodes of viral infection and during the clinical use of recombinant interferons, but there have been very few reports regarding the effect of active bacterial infections on cytochrome P450-mediated metabolism. The objective of this study was to determine the mechanism by which the Gram-positive bacteria Listeria monocytogenes causes a depression of cytochrome P450-mediated biotransformation in mice. After induction with beta-napthoflavone, hepatic microsomal cytochrome P450 levels were reduced by 40% and ethoxyresorufin-O-dealkylase (EROD) activity was decreased by 65% in mice infected for 48 hr. The loss of EROD activity was accompanied by losses of cytochrome P450IA apoenzyme and cytochrome P450IA mRNA. Listeria infection did not affect total mRNA levels, as determined by oligo(dT)18 hybridization. The time course of these effects demonstrated that an up-regulation of cytochrome P450IA preceded the loss of this isozyme and that changes in cytochrome P450IA mRNA preceded the changes in apoenzyme levels and EROD activity. In hepatic microsomes from uninduced mice, cytochrome P450 levels and the rates of dealkylation of ethoxyresorufin, benzyloxyresorufin, pentoxyresorufin, and aminopyrine were significantly reduced, by 40-60%, after 48 hr of infection. The decrease in aminopyrine-N-demethylase activity was accompanied by a loss of cytochrome P450IID9 mRNA after 48 hr of infection. Cytochrome P450IID9 mRNA levels returned to normal after 96 hr of infection, whereas aminopyrine-N-demethylase activity was still decreased at this time. No up-regulation of cytochrome P450IID9 occured before the loss of this isozyme. The results of this study indicate that the changes in the levels of cytochrome P450IA and cytochrome P450IID9 that are observed during L. monocytogenes infection occur at a pretranslational step. If other bacteria have a similar capacity to depress cytochrome P450 by such a mechanism, then drugs with narrow therapeutic indices should be administered with caution during infectious diseases caused by bacteria or viruses.
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
S G
SG
Armstrong
K W
KW
Renton
D000818:Animals; D001711:Biotransformation; D015153:Blotting, Western; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D008088:Listeriosis / Q000201:enzymology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000201:enzymology*; D010088:Oxidoreductases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1