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.
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.
Hu
Rong
R
Graduate Program in Pharmaceutical Science, Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Shen
Guoxiang
G
Yerramilli
Usha Rao
UR
Lin
Wen
W
Xu
Changjiang
C
Nair
Sujit
S
Kong
Ah-Ng Tony
AN
D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects; D002083:Butylated Hydroxyanisole / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics; D006207:Half-Life; D008658:Inactivation, Metabolic / Q000235:genetics; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D000975:Antioxidants; D002083:Butylated Hydroxyanisole; D014453:Glucuronosyltransferase; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase; C491732:Nqo1 protein, mouse