| Autor: |
Roy P; Department of Comparative Biosciences, Center for Biophysics and Quantitative Biology, Beckman Institute for Advanced Science and Technology, Department of Bioengineering, Neuroscience program, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, United States.; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States., Dennis DG; Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States.; Cancer Center at Illinois, University of Illinois, Urbana, Illinois 61801, United States., Eschbach MD; Department of Comparative Biosciences, Center for Biophysics and Quantitative Biology, Beckman Institute for Advanced Science and Technology, Department of Bioengineering, Neuroscience program, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, United States.; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States., Anand SD; Department of Comparative Biosciences, Center for Biophysics and Quantitative Biology, Beckman Institute for Advanced Science and Technology, Department of Bioengineering, Neuroscience program, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, United States.; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States., Xu F; Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California 94143, United States., Maturano J; Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States.; Cancer Center at Illinois, University of Illinois, Urbana, Illinois 61801, United States., Hellman J; Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California 94143, United States., Sarlah D; Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States.; Cancer Center at Illinois, University of Illinois, Urbana, Illinois 61801, United States., Das A; Department of Comparative Biosciences, Center for Biophysics and Quantitative Biology, Beckman Institute for Advanced Science and Technology, Department of Bioengineering, Neuroscience program, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, United States.; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.; Cancer Center at Illinois, University of Illinois, Urbana, Illinois 61801, United States. |
| Abstrakt: |
The phytocannabinoid cannabigerol (CBG) is the central biosynthetic precursor to many cannabinoids, including Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). Though the use of CBG has recently witnessed a widespread surge because of its beneficial health effects and lack of psychoactivity, its metabolism by human cytochrome P450s is largely unknown. Herein, we describe comprehensive in vitro and in vivo cytochrome P450 (CYP)-mediated metabolic studies of CBG, ranging from liquid chromatography tandem mass spectrometry-based primary metabolic site determination, synthetic validation, and kinetic behavior using targeted mass spectrometry. These investigations revealed that cyclo-CBG, a recently isolated phytocannabinoid, is the major metabolite that is rapidly formed by selected human cytochrome P450s (CYP2J2, CYP3A4, CYP2D6, CYP2C8, and CYP2C9). Additionally, in vivo studies with mice administered with CBG supported these studies, where cyclo-CBG is the major metabolite as well. Spectroscopic binding studies along with docking and modeling of the CBG molecule near the heme in the active site of P450s confirmed these observations, pointing at the preferred site selectivity of CBG metabolism at the prenyl chain over other positions. Importantly, we found out that CBG and its oxidized CBG metabolites reduced inflammation in BV2 microglial cells stimulated with LPS. Overall, combining enzymological studies, mass spectrometry, and chemical synthesis, we showcase that CBG is rapidly metabolized by human P450s to form oxidized metabolites that are bioactive. |
