Study of the mechanism of metabolic activation of chloramphenicol by rat liver microsomes

Abstract

The mechanism of the metabolic activation of chloramphenicol (CAP) by a cytochrome P-450 enzyme system in liver microsomes of rats has been studied by measuring the covalent binding to microsomal protein of specifically labeled [ 14C] and [ 3H] derivatives of CAP. The lack of binding of dichloroacetic acid, CAP base, and the acetamido and trifluoroacetamido derivatives of CAP indicates that the diehloroacetamido group of CAP is required for activation. The binding of dichloroacetamide supports this conclusion. Moreover, the C—H bond of the dichloromethyl carbon of CAP appears to be broken in the activation process since the hydrogen is lost in covalent binding. These results are consistent with the view that CAP is activated by hydroxylation of the diehloroacetamido group followed by spontaneous dehydrochlorination to an oxamyl chloride which acylates microsomal protein. The possible pharmacologic and toxicologie importance of this oxidative dehalogenation process is discussed