Clinical and cellular effects of cytochrome P-450 modulators

Abstract

Stress stimulates the hypothalamic–pituitary–adrenal axis and leads to elevated glucocorticoid hormones (GCs). GCs reduce inflammation and suppress responses 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 arachidonic acid, implicating epoxygenases in regulating inflammation and the generation of fever. Intraperitoneal injection of lipopolysaccharide (LPS) triggers fever in rats and mice, and administration of compounds known to induce CYP reduces LPS-induced fever, while inhibitors of CYP suppress fever. Consistent with these findings, inhibitors of CYP augment the elevation of LPS-induced prostaglandin E2 levels, an endogenous pyrogen, and administration of epoxygenase metabolites results in antipyresis. CYP inducers also reduce lung inflammation, the resulting mucous cell metaplasia, and the percentage of Bcl-2-positive mucous cells in rat airways after intratracheal instillation of LPS. Together, these observations indicate that CYP modulators may have therapeutic anti-inflammatory effects, and this pathway may be involved in stress-induced reduction of inflammation.