Effects of BSO and L‐Cysteine on Drug‐Induced Cytotoxicity in Primary Cell Cultures: Drug‐, Cell Type‐, and Species‐Specific Difference

Abstract

The effects of DL‐buthionine‐(S,R)‐sulfoximine(BSO) and L‐cysteine(CYS) on cytotoxicity induced by cisplatin(CP) and diclofenac(DIC) in primary cell cultures of hepatocytes and renal tubular epithelial cells(RTEC) isolated from rats or monkeys were studied. Hepatocytes and RTEC were inoculated into collagen coated 96‐well culture plates. After preincubation, a series of concentrations of CP or DIC were added, and 16 h and 4 h prior to CP and DIC, 40 µM BSO and 5 mM CYS were added, respectively. MTT assays were performed to evaluate cytotoxicity(concentrations of drug that inhibited 50% cell growth, IC₅₀). CYS made IC₅₀s of CP in rat and monkey RTEC increase up to more than 5 mM, but BSO made IC₅₀s of CP in rat RTEC lower down with bigger magnitude than that in monkey RTEC; similarly, CYS made IC₅₀s of CP in rat hepatocytes increase up to more than 5 mM, but BSO made IC₅₀s lower down with bigger magnitude than that in rat RTEC. However, neither CYS nor BSO had significant effects on all IC₅₀s of DIC in all examined cells. These results suggested that during CP‐induced stress state, rat hepatocytes were more susceptible to changes of GSH level than rat RTEC, and rat RTEC were more dependent on intracellular GSH status than monkey RTEC. DIC‐induced cytotoxicity in RTEC and hepatocytes are independent of GSH level.

Key Words: :

• Cisplatin
• Diclofenac
• Renal tubular epithelial cells
• Hepatocytes
• Glutathione
• DL‐buthionine‐(S,R)‐sulfoximine
• L‐cysteine
• Rat
• Monkey