lipopolysaccharide, cytochrome P-450, drug metabolism
Central nervous system (CNS) infection and inflammation severely reduce the capacity of cytochrome P-450 metabolism in the liver. We developed a mouse model to examine the effects of CNS inflammation on hepatic cytochrome P-450 metabolism. FVB, C57BL/6, and C3H/HeouJ mice were given Escherichia coli LPS (2.5 μg) by intracerebroventricular (ICV) injection. The CNS inflammatory response was confirmed by the elevation of TNF-α and/or IL-1β proteins in the brain. In all mouse strains, LPS produced a 60–70% loss in hepatic Cyp3a11 expression and activity compared with saline-injected controls. Adrenalectomy did not prevent the loss in Cyp3a11 expression or activity, thereby precluding the involvement of the hypothalamic-adrenal-pituitary axis. Endotoxin was detectable (1–10 ng/ml) in serum between 15 and 120 min after ICV dosing of 2.5 μg LPS. Peripheral administration of 2.5 μg LPS by intraperitoneal 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 Toll-like receptor-4 (TLR4)-mutant (C3H/ HeJ) mice, indicating that TLR4 signaling pathways are directly involved in the enzyme loss. In summary, we conclude that LPS is transferred from the brain to the circulation in significant quantities in a model of CNS infection or inflammation. Subsequently, LPS that has reached the circulation stimulates a TLR4-dependent mechanism in the periphery, evoking a reduction in Cyp3a11 expression and metabolism in the liver.
Faculty of Applied Health & Community Studies
School of Applied Health
American Journal of Physiology - Gastrointestinal and Liver Physiology
Peer Reviewed/Refereed Publication
© 2005 the American Physiological Society
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Original Publication Citation
Goralski, K. B., Abdulla, D., Sinal, C. J., Arsenault, A., & Renton, K. W. (2005). Toll-like Receptor-4 Regulation of Hepatic Cyp3a11 Metabolism in a Mouse Model of LPS-induced CNS Inflammation. American Journal of Physiology - Gastrointestinal and Liver Physiology, 289(3), G434-G443. doi:10.1152/ajpgi.00562.2004
Goralski, Kerry B.; Abdulla, Dalya; Sinal, Christopher J.; Arsenault, Andre; and Renton, Kenneth W., "Toll-like Receptor-4 Regulation of Hepatic Cyp3a11 Metabolism in a Mouse Model of LPS-induced CNS Inflammation" (2005). Faculty Publications and Scholarship. 16.