Extent and persistence of streptozotocin-induced DNA damage and cell proliferation in rat kidney as determined by in vivo alkaline elution and BrdUrd labeling assays.
The extent of DNA damage and cellular proliferation induced in rat kidneys by single doses of the diabetogenic alkylating agent streptozotocin (STZ) and the time course of repair of that damage were evaluated using an in vivo alkaline elution assay for DNA strand breaks and a bromodeoxyuridine (BrdUrd) labeling assay for cell replication. Male Sprague-Dawley rats were given iv injections of 0.25 to 60 mg/kg STZ and kidneys were harvested 3 hr later for alkaline elution. A dose of 2.5 mg/kg STZ was the lowest dose to induce detectable DNA strand breaks and extensive damage was produced by the commonly used diabetogenic dose of 60 mg/kg. To characterize the repair of the drug-induced DNA damage, kidneys were harvested from a 60 mg/kg group of animals 3 hr to 27 days after dosing. BrdUrd-labeled kidney sections were also evaluated to assess any cellular proliferative response associated with STZ administration. Significant DNA damage was detected up to 14 days after dosing with return to near background levels by 20 days. Similarly, treatment with 60 mg/kg STZ was associated with increases in BrdUrd labeling indices 4 and 9 days after treatment with resolution by 27 days. These results indicate that the cellular and molecular repair responses to a single diabetogenic dose of STZ are prolonged, requiring up to 3 weeks to complete. Thus, to avoid potential additive or synergistic effects on STZ-induced nephrotoxicity and/or genotoxicity, a delay in the start of experimental therapies in this model (other than insulin) should be considered.
Department of Genetic and Cellular Toxicology, Merck Research Laboratory, West Point, Pennsylvania 19486, USA.
A R
AR
Kraynak
R D
RD
Storer
R D
RD
Jensen
M W
MW
Kloss
K A
KA
Soper
J H
JH
Clair
J G
JG
DeLuca
W W
WW
Nichols
R S
RS
Eydelloth
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001973:Bromodeoxyuridine / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002509:Cephaloridine / Q000494:pharmacology; D004247:DNA / Q000302:isolation & purification / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000633:toxicity*; D013997:Time Factors
D000900:Anti-Bacterial Agents; D013311:Streptozocin; D004247:DNA; D001973:Bromodeoxyuridine; D002509:Cephaloridine