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IJ Lee, KS Jeong, BJ Roberts, AT Kallarakal, P Fernandez-Salguero, FJ Gonzalez and BJ Song
Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20852, USA. ijlee@dicbr.niaaa.nih.gov
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.
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