Induction of CYP2B6 and CYP3A4 expression by 1-aminobenzotriazole (ABT) in human hepatocytes

Drug Metab Lett. 2010 Aug;4(3):129-33. doi: 10.2174/187231210791698410.

Abstract

1-Aminobenzotriazole (ABT) has been widely used in drug development process as an irreversible inhibitor of CYP enzymes. One potential use of ABT is to potentiate pharmacological effects of rapidly-metabolized drugs on CYP expression by inhibiting their metabolism; however, ABT's own effects on CYP expression have been unknown. In this study, we show that ABT up-regulates expression of CYP2B6 and CYP3A4 potentially by activating nuclear receptor CAR. In freshly isolated human hepatocytes, ABT increased mRNA expression of CYP2B6 and CYP3A4 in a concentration-dependent manner. ABT also modulated CYP-inducing actions of CITCO and rifampin, the known inducers of CYP2B6 and CYP3A4. Results from luciferase reporter assays confirmed that ABT increases CYP2B6 promoter activity in CAR-expressing HepG2 cells. These results suggest that the use of ABT as a potentiator of pharmacological effects of rapidly-metabolized drugs is limited due to its own pharmacological actions on CYP expression as a CAR activator.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aryl Hydrocarbon Hydroxylases / biosynthesis*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A / biosynthesis*
  • Cytochrome P-450 CYP3A / genetics
  • Dose-Response Relationship, Drug
  • Enzyme Induction
  • Gene Expression Regulation, Enzymologic / drug effects
  • Hep G2 Cells
  • Hepatocytes / drug effects*
  • Hepatocytes / enzymology
  • Humans
  • Oxidoreductases, N-Demethylating / biosynthesis*
  • Oxidoreductases, N-Demethylating / genetics
  • Oximes / pharmacology
  • Promoter Regions, Genetic / drug effects
  • RNA, Messenger / biosynthesis
  • Receptors, Cytoplasmic and Nuclear / drug effects
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Rifampin / pharmacology
  • Thiazoles / pharmacology
  • Transcriptional Activation / drug effects
  • Transfection
  • Triazoles / pharmacology*

Substances

  • Oximes
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • Triazoles
  • 1-aminobenzotriazole
  • constitutive androstane receptor
  • 6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Oxidoreductases, N-Demethylating
  • Rifampin