Transcriptional induction of the cytochrome P4501A1 gene by a thiazolium compound, YH439.

Abstract

The molecular mechanism of induction of cytochromes P4501A1/2 (CYP1A1/2) by a synthetic compound YH439 was studied in rodents as well as in cultured hepatoma cells. CYP1A1-mediated ethoxyresorufin-O-deethylase activity and amounts of its immunoreactive protein were increased in a time- and concentration-dependent manner after a single dose of YH439 (150 mg/kg). Northern blot analyses revealed that YH439 rapidly increased (< or = 2 hr) the levels of CYP1A1/2 mRNAs, resulting in an increase in CYP1A protein level by > 6-fold at 8 hr after injection. After YH439 administration, the levels of CYP1A1 and CYP1A2 mRNAs peaked at 8 hr and 16 hr, respectively, before returning to control levels at 16 and 24 hr. The CYP1A protein level, on the other hand, reached a maximum at 24 hr after YH439 treatment and returned to near-control levels at 72 hr. Nuclear run-on analyses revealed that YH439 induces CYP1A1/2 gene transcription as early as 2 hr after YH439 treatment. Cytosolic electrophoretic mobility shift assays suggested that YH439 activates the CYP1A1/2 genes through the aryl hydrocarbon (Ah) receptor and the xenobiotic response elements. The dependency on the Ah receptor for the induction of CYP1A1/2 by YH439 was confirmed by the lack of CYP1A1/2 induction in the Ah receptor knock-out mice (Ahr-1-) as well as in murine hepatoma cells without a functional Ah receptor. Molecular structural analysis of YH439 and several other compounds indicated that the planarity and size of a molecule are important in its interaction with the Ah receptor and subsequent CYP1A1/2 induction. YH439 is a thiazolium compound with little aromaticity and with a two-dimensional structure different from that of the Ahs. Therefore, it represents a new class of Ah receptor ligand and CYP1A inducer.

• Authors: I J Lee, K S Jeong, B J Roberts, A T Kallarakal, P Fernandez-Salguero, F J Gonzalez, B J Song
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 49 Issue 6 Pg. 980-8 (Jun 1996) ISSN: 0026-895X [Print] United States
• PMID: 8649358 (Publication Type: Journal Article)

Chemical References

• Malonates
• RNA, Messenger
• Receptors, Aryl Hydrocarbon
• Thiazoles
• YH 439
• Cytochrome P-450 Enzyme System
• Oxidoreductases
• Cytochrome P-450 CYP1A2
• diisopropyl 1,3-dithiol-2-ylidenemalonate

Topics

• Animals
• Base Sequence
• Cytochrome P-450 CYP1A2
• Cytochrome P-450 Enzyme System (biosynthesis, genetics)
• Dose-Response Relationship, Drug
• Electrophoresis
• Enzyme Induction (drug effects)
• Humans
• Male
• Malonates (pharmacology)
• Mice
• Molecular Sequence Data
• Oxidoreductases (biosynthesis)
• RNA, Messenger (analysis)
• Rats
• Rats, Sprague-Dawley
• Receptors, Aryl Hydrocarbon (physiology)
• Thiazoles (pharmacology)
• Transcription, Genetic (drug effects)
• Tumor Cells, Cultured