Central nervous system infection/inflammation severely reduces the capacity of cytochrome P450 metabolism in the liver. We have developed a mouse model to examine the effect of CNS inflammation on hepatic cytochrome P450 metabolism. FVB, C57/Bl/6 or C3H/HeouJ mice were given E.coli LPS (2.5 µg) by intracranial ventricular injection (i.c.v.). The CNS inflammatory response was confirmed by the elevation of TNF and/or IL-1 proteins in the brain. In all mouse strains, LPS produced a 60-70% loss in hepatic Cyp3a11 expression and activity compared to saline-injected controls. Adrenalectomy did not prevent the loss in Cyp3a11 expression/activity, thereby precluding the involvement of the HPA axis. Endotoxin was detectable (1-10 ng ml-1) in serum between 15 and 120 min after i.c.v. dosing of 2.5 µg of LPS. The administration of 2.5 µg of LPS by i.p. injection produced similar serum endotoxin levels and a similar loss (60%) in Cyp3a11 expression and activity in the liver. The loss of Cyp3a11 in response to centrally or peripherally administered LPS could not be evoked in TLR4 mutant (C3H/HeJ) mice indicating that TLR4 receptor-signaling pathways are directly involved in the enzyme loss. In summary, it is concluded that LPS is transferred from the brain to the circulation in significant quantities in a model of CNS infection/inflammation. Subsequently, LPS that has reached the circulation stimulates a TLR4 receptor mechanism in the periphery that evokes a reduction in Cyp3a11 expression and metabolism in the liver.