A role for cytokines as mediators of the depression in cytochrome P450 activity in brain and liver during CNS inflammation is proposed. Lipopolysaccharide (LPS) was given directly into the lateral ventricle of the brain to mimic a localized CNS infection. CYP1A activity and protein in both brain and liver were depressed in response to this treatment. The administration of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interferon-gamma (IFN-gamma) directly into the lateral ventricle emulated the effects of LPS on CYP1A activity only in the brain. In contrast, these centrally administered cytokines did not produce a concomitant loss of CYP1A activity in the liver. Significant levels of several cytokines (TNF-alpha, IL-1beta, and IFN-gamma) were produced in the serum of animals following intracerebroventricular (i.c.v.) administration of LPS. This production of peripheral cytokines by LPS could not be mimicked by the i.c.v. injection of IL-1beta or TNF-alpha. These results suggest that induction of cytokines in the brain may play a direct role in the depression of CYP1A activity in the CNS following the administration of LPS into the lateral ventricle. The production of cytokines within the brain does not appear to participate in the signaling process in the brain that leads to the concomitant loss of CYP1A activity in the liver. The subsequent production of cytokines in peripheral tissues, however, does appear to play a role in the loss of cytochrome P450 in the liver.