Hepatic cytochrome P-450 expression in tumor necrosis factor-alpha receptor (p55/p75) knockout mice after endotoxin administration

Hepatic cytochromes P-450 (CYP) are well characterized drug and xenobiotic metabolizing enzymes that are extensively regulated by genetic and environm ental factors. Inflammatory mediators, including interleukins (ILs), interf erons (IFNs), and tumor necrosis factor-alpha (TNF-alpha), have been shown to downregulate several CYP isoforms; however, elucidation of the inflammat ory mediators that are responsible for specific CYP down-regulation is diff icult. The purpose of this experiment was to evaluate the role endogenous T NF-alpha plays in the regulation of liver CYP expression after endotoxin ad ministration. Mice deficient in the p55 and p75 TNF receptors and wild-type mice were given Gram-negative bacterial lipopolysaccharide (LPS) and kille d 24 h after administration. CYP analysis indicates that LPS decreases CYP1 A, CYP2B, CYP3A, and CYP4A independently of TNF-alpha. CYP2D9 and CYP2E1 ac tivities show differential responses to LPS between wild-type and TNF p55/p 75 receptor knockout mice, indicating the down-regulation of CYP2D9 and CYP 2E1 is differentially modulated by TNF-alpha expression. Furthermore, TNF-a lpha appears to affect the constitutive expression of CYP2D9 and CYP2E1. To date, this is the first evidence suggesting that a proinflammatory cytokin e is involved in the constitutive regulation of drug-metabolizing enzymes.