Nitric oxide mediates an LPS-induced depression of cytochrome P450 (CYP1A) activity in astrocytes.
During inflammatory responses in the brain, the expression of cytochrome P450 isoforms in the CNS are modulated and the capacity of the brain to metabolize drugs and to synthesize or degrade certain endogenous chemicals and drugs is diminished. While this response can be attributed in part, to the production and action of cytokines within the brain, it is also likely that other inflammatory mediators play an integral role. This paper investigates a potential role for nitric oxide (NO) in the loss of cytochrome P450 (CYP1A) in the brain during inflammation. Escherichia coli lipopolysaccharide (LPS), a commonly used proinflammatory endotoxin, was incubated with cultured rat astrocytes to provide a model of inflammation in the CNS. CYP1A activity was significantly decreased in cultured astrocytes incubated with LPS for 24 h. This loss in enzyme activity was accompanied by a substantial production of nitric oxide (NO) by these cells. Immunohistochemical examination demonstrated an upregulation of inducible nitric oxide synthase (iNOS) expression following the exposure of astrocytes to LPS. The addition of a selective iNOS blocker (1400W) caused a partial but significant reversal of the LPS-mediated loss in CYP1A. The incubation of astrocytes with the NO-generating compound (DETA NONOate) resulted in a loss of CYP1A. Taken together, these observations suggest that NO plays a pivotal role in the inflammation mediated loss in CYP1A activity in the brain.
Nicholson
Tara E
TE
Department of Pharmacology, Sir Charles Tupper Medical Bldg. Dalhousie University Halifax, Nova Scotia, Canada, B3H 4H7.
Dibb
Sandra
S
Renton
Kenneth W
KW
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001596:Benzylamines / Q000494:pharmacology; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009603:Nitroso Compounds / Q000494:pharmacology; D051381:Rats
D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019363:Cytochrome P-450 CYP1A1