Clinical and cellular effects of cytochrome P-450 modulators

Stress stimulates the hypothalamic-pituitary-adrenal axis and leads to elev ated glucocorticoid hormones (GCs). GCs reduce inflammation and suppress re sponses mediated by cytokines, including fever and pulmonary inflammation. Besides cyclooxygenases and lipoxygenases, cytochrome P-450 enzymes (CYP), referred to as epoxygenases, are also involved in the metabolism of arachid onic acid, implicating epoxygenases in regulating inflammation and the gene ration of fever. Intraperitoneal injection of lipopolysaccharide (LPS) trig gers fever in rats and mice, and administration of compounds known to induc e CYP reduces LPS-induced fever, while inhibitors of CYP suppress fever. Co nsistent with these findings, inhibitors of CYP augment the elevation of LP S-induced prostaglandin E2 levels, an endogenous pyrogen, and administratio n of epoxygenase metabolites results in antipyresis. CYP inducers also redu ce lung inflammation, the resulting mucous cell metaplasia, and the percent age of Bcl-2-positive mucous cells in rat airways after intratracheal insti llation of LPS. Together, these observations indicate that CYP modulators m ay have therapeutic anti-inflammatory effects, and this pathway may be invo lved in stress-induced reduction of inflammation. (C) 2001 Elsevier Science B.V. All rights reserved.