Lx. Cui et al., EFFECT OF NUCLEOSIDE ANALOGS ON NEURITE REGENERATION AND MITOCHONDRIAL-DNA SYNTHESIS IN PC-12 CELLS, The Journal of pharmacology and experimental therapeutics, 280(3), 1997, pp. 1228-1234
The effects of several anti-human immunodeficiency virus nucleoside an
alogs were examined on neurite regeneration and mitochondrial DNA (mtD
NA) synthesis in nerve growth factor-primed PC-12 cells. Under pharmac
ologically relevant concentrations, the exposure of cells to 2',3'-did
eoxyinosine (ddl), 2',3'-dideoxycytidine (ddC) and 2',3'-didehydro-3'-
deoxythymidine (d4T) led to a marked dose-dependent inhibition of neur
ite regeneration with a 50% inhibitory concentration approximating 1,5
and 15 mu M, respectively. In contrast, 3'-azido-3'-deoxythymidine (A
ZT) and beta-L-2',3'-dideoxy-3'-thiacytidine (3TC) had no effect on ne
urite regeneration. Inhibition of mtDNA synthesis by ddl was dose depe
ndent, and ddC at a concentration of 10 mu M strongly reduced mtDNA co
ntent by >75%. However, no inhibition of mtDNA synthesis was detected
in cells exposed to 10 mu M 3TC or d4T and to 25 mu M AZT, suggesting
a lack of definite correlation between mtDNA depletion and blockage of
neurite regeneration. High performance liquid chromatographic analysi
s demonstrated that AZT, ddC, 3TC and d4T were anabolized to their res
pective monophosphate, diphosphate and triphosphate derivatives in the
PC-12 cells. In addition, d4T was phosphorylated to form its monophos
phate, diphosphate and triphosphate derivatives in isolated mitochondr
ia, whereas ddC was metabolized only to its monophosphate form and no
phosphorylated metabolites of 3TC were detected under the same conditi
ons. In summary, the peripheral neuropathy induced by ddC and ddl in p
atients with acquired immune deficiency syndrome may be accounted for
by the depletion of mtDNA content in the neurons. As for d4T, some oth
er mechanism(s) may be involved in its clinical neurotoxicity. Both AZ
T and 3TC lacked any substantial toxicity in our in vitro model, which
is in agreement with the clinical action of these drugs.