Is CYP1A1 induction always related to AHR signaling pathway?
Humans are daily subjected to ever increasing amounts of exogenous compounds. Some of them are capable of inducing cytochrome P450s, a process that allows the cell to adapt to changes in its chemical environment. One of the most widely CYP studied is CYP1A1 because it metabolises a large number of xenobiotics to cytotoxic and/or mutagenic derivatives. To date, results from the literature indicate that induction of CYP1A1 does not only involve the classical activation cascade of the Ah receptor, e.g. binding of the ligand to the AhR, heterodimerisation with Arnt protein, constitution of a complex with XRE responsive element and subsequent gene activation. Indeed, some xenobiotics do activate CYP1A1 gene expression in spite of their inability to compete with TCDD for binding to the AhR. Other signaling pathways must therefore also be considered. Firstly, the CYP1A1 inducer compounds could be very weak AhR ligands or may be metabolized into a form which is in turn capable of binding to the Ah receptor. A second hypothesis would be that these molecules could act through other signaling cascades. At this time, two of them seem to be implicated. One concerns the RARs signal transduction pathway, as already described for retinoic acid. The second may involve tyrosine kinase activation, but the precise relationship between this activation and CYPA1 induction remains yet to be established. For the moment there is still a black box which needs to be investigated.
Delescluse
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C
Laboratoire de Pharmaco-Toxicologie Cellulaire et Moléculaire, INRA, Centre de Recherches, 41 Bd du Cap, 06606, Antibes, France.
Lemaire
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G
de Sousa
G
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Rahmani
R
R
D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000502:physiology; D006801:Humans; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1