Fast regulation of cytochrome P450 activities by phosphorylation and consequences for drug metabolism and toxicity.
In contrast to the well-known regulation of cytochrome P450 (CYP) activity by enzyme induction, which represents a process with slow onset and slow offset, more recent studies revealed phosphorylation as a fast (within observation instantaneous) and isoenzyme-selective regulation. The phosphorylated enzyme (investigated isozyme: CYP2B1) was fully inactive. The phosphorylation is mediated by PKA and hence under control of hormones and drugs that alter cellular cAMP levels. The consequences for the metabolic control of toxic species derived from drugs and environmental carcinogens are discussed. This information will help to improve therapy with drugs metabolized by CYPs which are phosphorylated by PKA, especially if these drugs possess a narrow window between required effectiveness and unacceptable toxicity.
Oesch-Bartlomowicz
Barbara
B
Institute of Toxicology, University of Mainz, D-55131 Mainz, Germany
Oesch
Franz
F
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D006728:Hormones / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010766:Phosphorylation
D002273:Carcinogens; D006728:Hormones; D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D000242:Cyclic AMP; D019362:Cytochrome P-450 CYP2B1; D017868:Cyclic AMP-Dependent Protein Kinases