752 - Effect of Vigabatrin, an antiepileptic drug inhibitor of gamma-aminobutyric transaminase, on levels of deoxynucleotide triphosphate pools and a possible role in mitochondrial deficiency diseases.

Objectives: Vigabatrin is an antiepileptic drug approved by the FDA as monotherapy for a form of epilepsy in infants. Vigabatrin selectively and irreversibly inactivates the gamma-aminobutyric transaminase (ABAT) in the CNS. Current safety concerns include the risk of vision loss and suicidal thoughts. ABAT catalyzes the conversion of GABA into succinic semialdehyde and L-glutamate and has been reported to play a dual role in converting deoxynucleoside diphosphates (dNDPs) to deoxynucleoside triphosphates (dNTPS) as part of the mitochondrial nucleoside diphosphokinase (NDPK) complex. In ABAT deficiencies, elevation of GABA is found within the brain and CSF and research suggests possible deficiencies of mtDNA in tissues. The goal of this study was to directly evaluate the effect of vigabatrin on the conversion of dNDPs to dNTPs, and its potential for causing mtDNA depletion.

Design: Mitochondria from rat liver or immortal retinal cells (661W) cultured in a quiescent state for 10 days in the presence and absence of vigabatrin (300 mM) were incubated with [3H]-thymidine for 60 min in the presence and absence of vigabatrin (300 mM). The conversion to [3H]-TMP, -TDP, and -TTP were measured by standard methods. MtDNA and genomic DNA were quantitated in quiescent retinal cells cultured for 10 days + and – vigabatrin using the ScienCell mtDNA kit #M8948.

Results: The results show that [3H]-thymidine was readily converted to [3H]-TTP in both isolated liver mitochondria and in the quiescent retinal cells, and that vigabatrin had no effect on the conversion. Further, vigabatrin did not appear to decrease the level of mtDNA in quiescent cells incubated with vigabatrin for 10 days.

Conclusions: Our data indicates using direct radiochemical conversion that vigabatrin does not inhibit the conversion of [3H]-TDP to [3H]-TTP and does not inhibit NDPK. Further, we could not show that vigabatrin caused mtDNA depletion in 661W cells as previously reported.