Comparative interactions of streptozotocin and chlorozotocin with DNA of an insulin-secreting cell line (RINr).
Both streptozotocin and chlorozotocin, the 2-chloroethyl analogue of streptozotocin, are diabetogenic chemicals in rodents. Although these chemicals are similar structurally, they appear to act on pancreatic B cells via different mechanisms. In studies here, damage and repair of DNA after exposure of an insulin-secreting cell line to streptozotocin and chlorozotocin were assessed by nucleoid sedimentation and alkaline elution. Equitoxic concentrations of streptozotocin and chlorozotocin caused significant single-strand breakage of DNA (p less than 0.005). These lesions were repaired in a time-dependent manner, with most repair completed by 24-h post-exposure to chemicals. Additionally, chlorozotocin caused DNA-DNA and DNA-protein crosslinks in insulinoma cells. When proteinase K was included in the crosslinking assay, a substantial proportion of the chlorozotocin-associated crosslinks proved to be DNA interstrand in nature. Analysis of the amount of interstrand crosslinking in insulinoma cells after exposure to chlorozotocin for 1 h showed that formation of interstrand crosslinks was slow. Increasing amounts appeared over a 24-h period. These results suggest that the formation of irreversible DNA interstrand crosslinks may be a critical factor in cytotoxicity and diabetogenicity caused by chlorozotocin.
D000478:Alkylation; D000818:Animals; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D007340:Insulinoma / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects*; D051381:Rats; D013311:Streptozocin / Q000031:analogs & derivatives* / Q000633:toxicity*
C007028:chlorozotocin; D013311:Streptozocin; D004247:DNA