The role of cytokines in the depression of CYP1A activity using cultured astrocytes as an in vitro model of inflammation in the central nervous system.
The interaction and modulation of hepatic cytochrome P450 enzymes by infection and inflammation has been well described both in clinical settings and in animal models. Recent evidence found that inflammation in the central nervous system (CNS) leads to alterations in cytochrome P450 activity in both brain and liver. The bacterial endotoxin lipopolysaccharide (LPS) was used to induce an inflammatory response in cultured astrocytes as a model of CNS inflammation. This inflammatory response involves a range of immune mediators, such as acute phase cytokines, nitric oxide, prostanoid products, and reactive oxygen species. It is hypothesized that cytokines, released during inflammation, act to modulate the expression of specific isoforms of cytochrome P450 resulting in altered activity levels. High levels of the cytokines tumor necrosis factor-alpha and interleukin-1beta were released into culture medium after the addition of LPS to astrocyte cultures. When these same cytokines were added directly to the cultures, they also were able to modulate levels of CYP1A activity. The concurrent addition of dexamethasone to astrocytes blocked both the cytokine release and the alteration of CYP1A activity, thus supporting a role for these cytokines in this response. These results provide evidence suggesting an involvement of acute phase cytokines in mediating the LPS-induced depression of CYP1A activity in cultured astrocytes.
Nicholson
Tara E
TE
Department of Pharmacology, Sir Charles Tupper Medical Bldg., Dalhousie University, Halifax, Nova Scotia, B3H 4H7 Canada.
Renton
Kenneth W
KW
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001253:Astrocytes / Q000201:enzymology / Q000378:metabolism*; D001927:Brain Diseases / Q000378:metabolism; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation; D004790:Enzyme Induction; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D003907:Dexamethasone; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2