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Phosphorylation of xenobiotic-metabolizing cytochromes P450

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Abstract

The regulation of cytochromes P450 (CYPs) by induction mediated by xenobiotics is well known. Our team has discovered an additional important regulation of xenobiotic-metabolizing CYPs by phosphorylation. Individual CYPs are phosphorylated by different protein kinases, leading to CYP isoenzyme-selective changes in the metabolism of individual substrates and consequent profound changes in the control of mutagenic and cytotoxic metabolites. Some CYPs are phosphorylated by protein kinase C and some by the cyclic adenosine monophosphate (cAMP) dependent protein kinase A. We found that cAMP not only leads to drastic changes in the activity of individual CYPs, but also drastic changes in the nuclear localization of the CYP-related transcription factor Ah receptor (AHR). The consequences are very different from those of AHR nuclear translocation mediated by its classic ligands (such as dioxin and many polycyclic aromatic hydrocarbons) and may represent the long-sought physiological function of the AHR. The disturbance of this physiological function of AHR by extremely persistent high-affinity xenobiotic ligands such as dioxin may represent the most important contributing factor for their potent toxicity.

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Abbreviations

AHR:

Ah receptor

ARNT:

Ah receptor nuclear translocator

cAMP:

cyclic adenosine monophosphate

cDNA:

complementary DNA

CYP:

cytochrome P450

dbcAMP:

N 6,O 2′-dibutyryl cyclic adenosine monophosphate

PKA:

protein kinase A

PKC:

protein kinase C

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Acknowledgements

The authors thank the EU Network of Excellence ECNIS (Environmental Cancer, Nutrition and Individual Susceptibility) operating within the EU Sixth Framework Programme, Priority 5: “Food Quality and Safety” (contract no. 513943) for support.

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Authors and Affiliations

  1. ECNIS Section, Johannes Gutenberg University, 55131, Mainz, Germany

    B. Oesch-Bartlomowicz & F. Oesch

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  1. B. Oesch-Bartlomowicz
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  2. F. Oesch
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Correspondence to B. Oesch-Bartlomowicz.

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Oesch-Bartlomowicz, B., Oesch, F. Phosphorylation of xenobiotic-metabolizing cytochromes P450. Anal Bioanal Chem 392, 1085–1092 (2008). https://doi.org/10.1007/s00216-008-2315-2

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  • DOI: https://doi.org/10.1007/s00216-008-2315-2

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