Transcriptional and post-translational regulation of CYP1A1 by primaquine.

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Werlinder V, Backlund M, Zhukov A, Ingelman-Sundberg M

Transcriptional and post-translational regulation of CYP1A1 by primaquine.

J Pharmacol Exp Ther. 2001 Apr;297(1):206-14.

PubMed ID

11259546 [ View in PubMed

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Abstract

Regulation of the CYP1A1 gene has been shown to involve the aryl hydrocarbon receptor and the CYP1A1 gene expression is induced by AhR ligands. Primaquine is an antimalarial agent that does not exhibit the structural properties of a classical AhR ligand. We have evaluated the mechanisms by which this compound induces CYP1A1 expression using rat hepatoma H4IIE cells and V79 cells stably expressing CYP1A1. In H4IIE cells, primaquine caused a time- and dose-dependent increase of CYP1A1 mRNA and protein expression. The transcriptional activation of the CYP1A1 gene by primaquine was strictly XRE-dependent, as shown by transfection of different CYP1A1 pGL3 reporter constructs in H4IIE cells, and the involvement of the AhR was shown by activation of a Gal4-AhR hybrid protein by primaquine in transfected cells. Furthermore, primaquine caused transformation of the cytosolic AhR to a DNA-binding form, in vitro, suggesting that primaquine directly activates the receptor complex. In addition to its action at the transcriptional level, primaquine caused a dose-dependent inhibition of CYP1A1 degradation with an IC(50) of 3.3 , as seen in mammalian V79 cells. This was not due to the lysosomotropic activity of the drug since other lysosomotropic agents were ineffective. Primaquine formed a type II binding spectrum with CYP1A1 and inhibited the CYP1A1-dependent ethoxyresorufin O-deethylase activity in vitro with a K(i) of 1.3 microM, which is close to the IC(50), suggesting that the drug protects CYP1A1 from degradation by binding at the active site. It is concluded that CYP1A1 is regulated by primaquine both on the transcriptional as well as on a post-translational level.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Primaquine	Cytochrome P450 1A1	Protein	Humans	Unknown	Inducer	Details