p38 Mitogen-activated Protein Kinase Negatively Regulates the Induction of Phase II Drug-metabolizing Enzymes That Detoxify Carcinogens

摘要: Phase II drug-metabolizing enzymes, such as glutathione S-transferase and quinone reductase, play an important role in the detoxification of chemical carcinogens. The induction these detoxifying enzymes by a variety agents occurs at transcriptional level is regulated cis-acting element, called antioxidant response element (ARE) or electrophile-response element. In this study, we identified signaling kinase pathway that negatively regulates ARE-mediated gene expression. Treatment human hepatoma HepG2 murine Hepa1c1c7 cells with tert-butylhydroquinone (tBHQ) stimulated activity p38, member mitogen-activated protein family. Inhibition p38 activation its inhibitor, SB203580, enhanced reductase ARE reporter tBHQ. contrast, SB202474, negative analog had little effect. Consistent result, interfering overexpression dominant-negative mutant MKK3, immediate upstream regulator potentiated tBHQ, whereas wild types MKK3 diminished activation. addition, inhibition augmented tert-butylhydroxyanisole, sulforaphane, beta-naphthoflavone. Thus, functions phase enzymes.