The effects of acute infection and inflammation on phase II detoxifying enzymes

Abstract

Infection and inflammation may alter liver metabolism causing significant changes in drug efficacy and toxicity. The expression and activity of the Cytochromes P450 in human liver are significantly down-regulated during acute infection and inflammation but little is known about Phase II metabolizing enzymes. We treated the human liver cell line HepG2 with TNF-α and IL-1β to at 0.1-1000 U/mL for 0-48 hours as a model of acute infection and inflammation. Cells were harvested at each time point and assessed for cell death (MIT assay) and levels of reactive oxygen species (ROS) and for the expression and activity of the major Phase II enzymes UDP-glucuronosyl transferase (UGT), Glutathione-S-transferase (GST) and Sulfotransferase (SULT). Since all of these enzymes have hepatic nuclear factor (HNF) recognition sequences in their genes, we assessed the effects of the cyrokines on HNF1 and HNF4 expression and nuclear translocation with immunofluorescence. UGT enzymes are not significantly affected by pro-inflammatory cytokines and SULT enzymes showed no change in activity while GST enzymes showed a significant increase in activity but returned to norma1levels by 48 hours. Higher GST activity may confer lower efficacy of drugs during acute infection and inflammation.