The evolution of our understanding of endo-xenobiotic crosstalk and cytochrome P450 regulation and the therapeutic implications.
BACKGROUND
Over the past years, there has been increasing evidence that, at least in vertebrates, cytochrome P450-dependent monooxygenases (CYPs) are governed by a most complex regulation. The respective mechanisms comprise structural features such as domain movements, allostery, enzyme-oligomerization as well as numerous transcription factors, non-coding RNAs and extensive regulatory crosstalk.


METHODS
This review summarizes the recent aspects of structural and molecular CYP regulation and discusses the respective consequences and implications. The authors, further, examine the evolutionary origins of CYP regulation in light of their role as endogenous and xenobiotic enzymes. Finally, the article aims to elucidate the potential of CYP regulation as a pharmaceutical target.


CONCLUSIONS
Studies on CYP regulation paint an increasingly complex picture of a layered set of regulatory mechanisms. These start structurally on single molecule level, continue with cooperativity and oligomerization of enzyme complexes and finally include a multifaceted regulation of expression control and crossregulation. The respective regulatory network is a key to cellular plasticity and adaptivity. However, it can also be the cause for pathological conditions as well as resistance to medical treatment. A better understanding of the regulatory aspects of CYP biology is, thus, not only of academic interest but promises to be highly rewarding. Even with the limited knowledge available, CYP regulation and CYP crosstalk are already promising pharmacological targets.
German Federal Institute for Risk Assessment (BfR), Department of Product Safety , Max-Dohrn Strasse 8-10, 10589 Berlin , Germany Tewes.Tralau@bfr.bund.de.
Tewes
T
Tralau
Andreas
A
Luch
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D019143:Evolution, Molecular; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D010084:Oxidation-Reduction; D011487:Protein Conformation; D015262:Xenobiotics
D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System