NEW PATHWAY OF METABOLISM OF CHLORAMPHENICOL WHICH INFLUENCES THE INTERPRETATION OF ITS IRREVERSIBLE BINDING TO PROTEIN INVIVO

The mechanism of the metabolic activation of chloramphenicol (CAP) in vivo in the rat has been studied by measuring the irreversible binding to protein of specifically labeled [1, 2-14C] dichloroacetamido and 1-3H-benzylic derivatives of CAP. In every tissue examined, the 14C-label of CAP bound significantly more than the 3H-label, indicating that only part of the structure of CAP was bound. When 14C-labeled plasma protein, from rats given [14C]CAP, was hydrolyzed chemically or enzymatically, glycine and serine were identified by thin-layer chromatography and reverse isotope dilution analysis as the predominant radioactive products. These results indicate that the majority of the irreversible binding of CAP to protein in vivo is not due to its metabolic activation into a reactive metabolite as was found in vitro in liver microsomes, but instead is due to its metabolism into small molecular fragments, which are incorporated into pools of normal tissue constituents. These small molecules are subsequently biosynthesized into glycine and serine, and these amino acids are then incorporated into the structure of tissue protein. The general importance of these results and possible pathways for the metabolism of CAP into glycine and serine are discussed. © 1979.