Abstract
DL- α-difluoromethylornithine (DFMO) is a specific, irreversible inhibitor of ornithine decarboxylase (ODC), the rate-limiting enzyme in trypanosome polyamine biosynthesis (reviewed in 1). DFMO cures experimental infections of African trypanosomiasis, and is in phase 1 clinical trials2. Although the mechanism of selective toxicity is incompletely known, DFMO has well known effects upon the metabolism and morphology of trypanosomes1. Following depletion of the polyamines, putrescine and spermidine, by DFMO, long slender trypomastigotes change into stumpy-like forms which are eliminated by the host. DFMO alters mitochondrial transcripts in these cells3, and reduces their trypanothione [T(SH)2] levels4. As reviewed elsewhere in this volume (Fairlamb, A.H.), T(SH)2 has two important roles in kinetoplastid metabolism: the maintenance of intracellular redox balance and protection against toxic oxygen derivatives and other radicals. The selective toxicity of DFMO for ODC in trypanosomes has also been attributed to this enzyme’s slower turnover rate than in mammalian cells5.
Published Version
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