Is CYP1A1 induction always related to AHR signaling pathway?

Humans are daily subjected to ever increasing amounts of exogenous compound s. Some of them are capable of inducing cytochrome P450s, a process that al lows the cell to adapt to changes in its chemical environment. One of the m ost widely CYP studied is CYP1A1 because it metabolises a large number of x enobiotics 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 ligan d to the AhR, heterodimerisation with Amt protein, constitution of a comple x 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 b e 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 th ese molecules could act through other signaling cascades. At this time, two of them seem to be implicated. One concerns the RARs signal transduction p athway, as already described for retinoic acid. The second may involve tyro sine kinase activation, but the precise relationship between this activatio n and CYPA1 induction remains yet to be established. For the moment there i s still a black box which needs to be investigated. (C) 2000 Elsevier Scien ce Ireland Ltd. All rights reserved.