Effect of β-enantiomeric and racemic nucleoside analogues on mitochondrial functions in HepG2 cells: Implications for predicting drug hepatotoxicity☆

摘要: Abstract A group of enantiomeric nucleoside analogues with β- d or l configuration, which represent potential candidates for the treatment hepatitis B virus (HBV) infection, were incubated in human hepato-blastoma HepG2 cells at concentrations between 0.1 and 10 μM 4–14 days. Then effects on mitochondrial DNA (mtDNA) content, lactic acid production, lipid droplet formation, morphology evaluated. No effect production was detected treated -2′,3′-dideoxy-3′-thiacytidine (3TC), -2′,3′-dideoxy-5-fluoro-3′-thiacytidine (β- -FTC), racemic cis 2′,3′-dideoxy-5-fluoro-3′-thiacytidine [(±)-FTC], 2,4- diamino -7-(2,3- dideoxy -2- fluoro -β- - arabinofuranosyl)pyrrolo [2,3-d] pyrimidine (T70178), whereas a slight increase associated -2-hydroxymethyl-5-(2,6-diaminopurin-9-yl)-1,3-dioxolane -DAPD) 4- amino -7-(2- deoxy -5- thiocarboxamide (T70182) μM. concentration-dependent observed exposed to [(±)-BCH-189], 2′,3′-dideoxy-3′-thiacytidine -2′,3′-dideoxy-5-fluorocytidine -FddC), -2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1, 3,-dioxolane -FDOC), (T70080), -2-nuoro-β- (T70179). Inhibition mtDNA content demonstrated be (+)-BCH-189, -FddC, T70080, 3TC, (±)-BCH-189, -FTC, (±)-FTC, -DAPD, T70178, T70179, T70182 had no effect. -FDOC resulted marked inhibition synthesis but not lower concentrations. Cells (±)- BCH -189, FTC , did show morphological changes compared control. In contrast, increased cytoplasmic droplets loss cristae mitochondria either -FDOC, T70080. (+)-BCH-189 mitochondria. summary, exhibited relatively safe profile, supporting their further development.