In vivo pharmacokinetics, activation of MAPK signaling and induction of phase II/III drug metabolizing enzymes/transporters by cancer chemopreventive compound BHA in the mice

Abstract

Phenolic antioxidant butylated hydroxyanisole (BHA) is a commonly used food preservative with broad biological activities, including protection against chemical-induced carcinogenesis, acute toxicity of chemicals, modulation of macromolecule synthesis and immune response, induction of phase II detoxifying enzymes, as well as its undesirable potential tumor-promoting activities. Understanding the molecular basis underlying these diverse biological actions of BHA is thus of great importance. Here we studied the pharmacokinetics, activation of signaling kinases and induction of phase II/III drug metabolizing enzymes/transporter gene expression by BHA in the mice. The peak plasma concentration of BHA achieved in our current study after oral administration of 200 mg/kg BHA was around 10 microM. This in vivo concentration might offer some insights for the many in vitro cell culture studies on signal transduction and induction of phase II genes using similar concentrations. The oral bioavailability (F) of BHA was about 43% in the mice. In the mouse liver, BHA induced the expression of phase II genes including NQO-1, HO-1, gamma-GCS, GST-pi and UGT 1A6, as well as some of the phase III transporter genes, such as MRP1 and Slcolb2. In addition, BHA activated distinct mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK), as well as p38, suggesting that the MAPK pathways may play an important role in early signaling events leading to the regulation of gene expression including phase II drug metabolizing and some phase III drug transporter genes. This is the first study to demonstrate the in vivo pharmacokinetics of BHA, the in vivo activation of MAPK signaling proteins, as well as the in vivo induction of Phase II/III drug metabolizing enzymes/transporters in the mouse livers.

Effect of dietary eugenol on xenobiotic metabolism and mediation of UDP-glucuronosyltransferase and cytochrome P450 1A1 expression in rat liver

“…Recent findings suggest that the cis-acting regulatory element and the antioxidant response element (ARE)/ electrophile response element (EpRE), play important roles in the transcriptional regulation of phase II genes, such as quinone oxidoreductase (EC 1.6.5.2), GST (EC 2.5.1.18) and UGT, by phenolic antioxidants (Kong et al, 2001;Rushmore & Kong, 2002;Xu et al, 2005). Several ARE/EpRE-binding proteins have been identified, including the members of basic leucine zipper transcriptional factor family, nuclear factor erythroid 2-related factor 1, 2 (Nrf1, Nrf2) and small Maf proteins (Buetler et al, 1995;Hu et al, 2006). Nrf2 is the most likely transcriptional factor involved in the transcriptional activation of ARE-mediated phase II genes by a phenolic antioxidant in Nrf2À/À mice studies (Maher & Yamamoto, 2010).…”

Dietary aloin, aloesin, or aloe-gel exerts anti-inflammatory activity in a rat colitis model

“…These results indicate that the inhibitory effect of aloin on DSS-induced colonic inflammation may be partly due to the inhibition of the ERK, JNK and p38 signaling pathways. Recently, Hu et al (2006) reported that the MAP kinase pathways may play an important role in early signaling events leading to the regulation of gene expression of phase II enzymes, including UGTs. We have previously demonstrated that aloesin is transformed to aloesin glucuronides/sulfates during intestinal absorption by UGT enzymes (Park et al 2009b), indicating that aloesin-regulated MAP kinase activity may also be involved in the absorption of aloesin.…”

Sulforaphane and erucin increase MRP1 and MRP2 in human carcinoma cell lines

“…Overexpression of P-gp and MRP1 appears to play a major role in the development of resistance, although this varies with cell type and the specific drugs concerned. Recent data indicate that Phase III detoxification transporters may be up-regulated in concert with Phase I and/or Phase II enzymes [10][11][12][13]. Thus, the system that improves defense against toxic compounds and aids in cancer prevention is the same as that found to be up-regulated in a variety of hematological and solid tumors expressing clinical drug resistance.…”