Isolation and identification of new rapamycin dihydrodiol metabolites from dexamethasone-induced rat liver microsomes

Xenobiotica. 1997 Sep;27(9):869-83. doi: 10.1080/004982597240055.

Abstract

1. Rapamycin is metabolically transformed in rat liver microsomes to 3,4- and 5,6-dihydrodiol metabolites under the influence of the cytochrome P-450 mixed function oxygenase system. These metabolites were produced from dexamethasone-induced as well as from non-induced rat liver microsomes. The comparison of the ion spray mass spectra of the 5,6-dihydrodiol with the 3,4-dihydrodiol of rapamycin shows clearly that dihydrodiols were formed in two distinct positions of rapamycin. 2. FAB mass spectra as well as electrospray mass spectra of two additional peaks isolated from the same chromatographic run confirm the presence of a 3,4-dihydrodiol metabolite of rapamycin as also strongly suggested by UV spectra. Hplc reinjection of each individual peak always resulted in chromatograms showing a combination of the same three peaks and therefore are to be considered as tautomers of the 3,4-dihydrodiol of rapamycin. 3. These tautomeric conformations were found to have no immunosuppressive potency, most probably due to important structural and stereochemical modifications of the rapamycin binding domain to the binding protein (FKBP-12) and/or to important metabolic structural modifications of rapamycin effector domain.

MeSH terms

  • Animals
  • Dexamethasone / administration & dosage
  • Immunosuppressive Agents / chemistry
  • Immunosuppressive Agents / isolation & purification*
  • Immunosuppressive Agents / metabolism
  • Isomerism
  • Male
  • Microsomes, Liver / chemistry*
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / metabolism
  • Polyenes / chemistry
  • Polyenes / isolation & purification*
  • Polyenes / metabolism
  • Rats
  • Rats, Wistar
  • Sirolimus
  • Spectrometry, Mass, Fast Atom Bombardment

Substances

  • Immunosuppressive Agents
  • Polyenes
  • Dexamethasone
  • Sirolimus