The potent anticarcinogenic effects of phenolic antioxidants 2(3)-tert- butyl-4-hydroxyanisole (BHA), and its demethylated active metabolite 2(3)-tert-butylhydroquinone (tBHQ), are partly attributed to potent induction of some phase 2 drug metabolizing enzymes such as glutathione S-transferases (GST), NAD(P)H: quinone oxidoreductases (NQO) and UDP-glucuronosyltransferases (UGT). However, the molecular mechanisms by which BHA and tBHQ induce phase 2 detoxifying enzymes, a potential chemopreventive action, have not been characterized. Recent studies from our laboratory and others have shown that the activity of a cellular signaling molecules, the mitogen-activated protein kinases (MAPKs), extracellular regulated kinase 2 (ERK2), c-Jun N-terminal kinase 1 (JNK1), or p38 can be enhanced by BHA and tBHQ, in a time- and dose-dependent fashion. The observations that modulation of one or more of these MAP kinase pathways by genetic or biochemical approaches, altered the level of expression of phase 2 NQO enzyme activity led us to propose the hypothesis that phenolic compounds such as BHA induce MAPK signaling pathway leading to phase 2 gene induction. The following specific aims are designed to test this hypothesis. (1) Determine the dose-dependent effect of BHA administration on the in vivo activation of MAPK and induction of phase 2 genes expression in mouse livers. (2) Determine the activation of MAPK pathways in hepatoma cell lines and in primary cultured of human and mouse hepatocytes in BHA-induced phase 2 NQO gene induction. (3) Determine the activation of transcription factor Nrf2 by MAPK pathways in BHA-induced phase 2 NQO gene induction. (4) Determine the phosphorylation of Nrf2 in BHA-induced phase 2 NQO gene induction. The results of our work will likely provide new information on (i) the role of signal transduction events in the regulation of phase 2 NQO gene expression by phenolic antioxidants such as BHA, and (ii) identification of the signaling pathway components that can be useful as chemopreventive agent design and screening targets.
Showing the most recent 10 out of 61 publications
