Species differences in nucleotide pool levels of 2',3'-dideoxycytidine: a possible explanation for species-specific toxicity.
The nucleoside analogue, 2',3'-dideoxycytidine (ddC), a potent inhibitor of human immunodeficiency virus reverse transcriptase (in its anabolized triphosphorylated form), mediates virologic and immunologic improvements in AIDS patients. Clinical studies using ddC have shown various ddC-related toxicities, the most pronounced being a dose-limiting peripheral neuropathy. The dose responsiveness and manifestation of the ddC-related neuropathy vary among species, with greatest sensitivity in human > monkey > rabbit whereas mice and rats are insensitive to ddC-related neuropathy. This study has examined nucleotide pool sizes of ddCTP and its constituents (ddC, ddCMP, ddCDP) in cultured fibroblasts (human, rabbit, mouse) and freshly isolated peripheral lymphocytes (monkey, rabbit, rat, and mouse). Cells were treated with 10 microM [3H]ddC and nucleotide pool sizes analyzed by HPLC. The formation of nucleotide pools increased during the 24-hr assay period. Fibroblast pool formation of phosphorylated metabolites was significantly greater in human > rabbit > mouse. Lymphocytes demonstrated a similar pattern with monkey > rabbit > mouse = rat. Total ddC anabolite pools were also found to be significantly smaller (p < 0.05) in rodent lymphocytes than in those of rabbit or monkey, and rodent fibroblasts were smaller than those of human or rabbit (p < 0.05). These findings indicate that nucleoside phosphorylation and intracellular levels of phosphorylated metabolites may play an important role in determining species sensitivity and manifestation of ddC-related toxicity.
Lipman
J M
JM
Department of Toxicology and Pathology, Hoffmann-La Roche Inc., Nutley, New Jersey 07110-1199.
Reichert
J A
JA
Davidovich
A
A
Anderson
T D
TD
D000818:Animals; D001711:Biotransformation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D008252:Macaca fascicularis; D051379:Mice; D010766:Phosphorylation; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D016047:Zalcitabine / Q000378:metabolism / Q000633:toxicity*
D016047:Zalcitabine