PMID: 11745470Dec 18, 2001Paper

cAMP-dependent phosphorylation of CYP2B1 as a functional switch for cyclophosphamide activation and its hormonal control in vitro and in vivo

International Journal of Cancer. Journal International Du Cancer
Barbara Oesch-BartlomowiczFranz Oesch

Abstract

An important feature of cytochrome P450 (CYP) 2B1 is its high ability to convert the prodrug cyclophosphamide (CPA) to therapeutically cytotoxic metabolites, resulting in interstrand DNA-cross-linking and cell death. We have examined whether and how the phosphorylation of CYP2B1 influences CPA metabolic activation in vitro and in vivo. We found first that only part of the total CYP2B1 pool undergoes phosphorylation. This part is fully inactivated. Second, phosphorylation of CYP2B1 in intact hepatocytes reduced by up to 75% toxification of CPA to mutagenic metabolites (totally dependent on the same preferentially CYP2B-catalyzed 4-hydroxylation of CPA as is the generation of highly cytotoxic species). Third, the phosphoacceptor-serine 128 of CYP2B1 in the consensus sequence for interaction with the protein kinase A represents an on/off switch for the activation of CPA depending on the phosphorylation conditions in the cell. Fourth, evidence is presented that the above-described events also occur in vivo. In conclusion, a successful therapy with CPA, helped by forced expression of CYP2B1 in tumor cells (as recently proposed) will, in addition, be profoundly modified by its phosphorylation status.

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Citations

Aug 16, 2008·Analytical and Bioanalytical Chemistry·B Oesch-Bartlomowicz, F Oesch
Jun 7, 2005·Mutation Research·M R Gomes-CarneiroFrancisco J R Paumgartten
Mar 18, 2004·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Ingrid Fleming
Aug 17, 2010·Asian Journal of Andrology·Shahriar Koochekpour
Dec 5, 2002·Archives of Biochemistry and Biophysics·Barbara Oesch-Bartlomowicz, Franz Oesch
Mar 3, 2004·Archives of Biochemistry and Biophysics·Barbara Oesch-Bartlmowicz, Franz Oesch
Jun 4, 2005·Drug Metabolism Reviews·Mike AguiarBernard F Gibbs
Nov 7, 2007·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Wolfgang W HuberRolf Schulte-Hermann
Dec 15, 2004·Toxicology·Vladimir O PustylnyakVyacheslav V Lyakhovich
Dec 14, 2006·Prostaglandins & Other Lipid Mediators·Ingrid Fleming
Oct 15, 2005·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·M R Gomes-CarneiroFrancisco J R Paumgartten
Sep 3, 2005·Biochemical and Biophysical Research Communications·B Oesch-Bartlomowicz, F Oesch
Sep 13, 2005·Toxicology·Vladimir O PustylnyakVyacheslav V Lyakhovich
Feb 18, 2017·Molecular Pharmaceutics·Jie GaoHai-Ling Qiao
Feb 18, 2021·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Franz OeschThomas Efferth

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