Regulation of cytochrome P450 IID by acute phase mediators in C3H/HeJ mice

Abstract

Cytochrome P450 IID6 is a drug metabolizing enzyme and the major target antigen in LKM-1 antibody positive chronic active hepatitis. The histological hallmark of chronic active hepatitis is a lymphocytic infiltrate in the liver. It is unknown whether and how cytokines produced and secreted by these tissue infiltrating mononuclear cells regulate the cellular expression of cytochrome P450 IID6. To study the effect of interleukin 1, tumor necrosis factor and interleukin 6 on the hepatocellular RNA expression of cytochrome P450 IID, we injected each of the cytokines in C3H/HeJ mice. We found a time-dependent suppression of the cytochrome in the liver. Six hours after the intraperitoneal injection of 0.5 micrograms interleukin 1 beta the specific RNA-expression was reduced to 25% of the original level. A similar reduction was found after the injection of 2 micrograms tumor necrosis factor alpha. A mild suppression to 65% of the original level was seen six hours following the dose of 100 ng interleukin 6. Our studies show how immune mediators can change the expression of an autoantigen. Further studies in the human system are necessary to estimate this regulation for the elimination of drugs and in LKM-1 antibody positive chronic active hepatitis.