Oxidative DNA base damage in renal, hepatic, and pulmonary chromatin of rats after intraperitoneal injection of cobalt(II) acetate.
DNA base damage was studied in renal, hepatic, and pulmonary chromatin of male and female F344/NCr rats that had been given either 50 or 100 mumol of Co(II) acetate/kg body wt in a single ip dose and killed 2 or 10 days later. Control rats received 200 mumol of sodium acetate/kg body wt. Chromatin was isolated from organs and analyzed by gas chromatography/mass spectrometry with selected ion monitoring. The following 11 products derived from purine and pyrimidine bases in DNA were quantified: 5-hydroxy-5-methylhydantoin, 5-hydroxyhydantoin,5-(hydroxymethyl)uracil(5-OHMe-Ura),5- hyd roxycytosine(5-OH- Cyt),thymine glycol, 5,6-dihydroxycytosine,4,6-diamino-5-formamido-pyrimidine (FapyAde),2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua),7,8-dihydro-8-oxoadenine,2-oxoadenine, and 7,8-dihydro-8-oxoguanine. The response was organ-specific. Eight of the DNA base products in renal chromatin of Co(II)-treated rats (mostly 5-OH-Cyt and other pyrimidine products), five in hepatic chromatin (mostly FapyGua and other purine products), and two in pulmonary chromatin (5-OHMe-Ura > FapyAde) were increased by 30% to more than 200% over control levels with increasing Co(II) dose. The renal and hepatic, but not pulmonary, DNA base damage tended to increase with time. No significant differences in response were found between male and female rats. The bases determined were typical products of hydroxyl radical attack on DNA, suggesting a role for this radical in the mechanism(s) of DNA damage caused by Co(II) in vivo. Some of these bases have been shown previously to be promutagenic. The present results imply involvement of oxidative DNA base damage in Co(II)-induced genotoxic and carcinogenic effects.
Kasprzak
K S
KS
Laboratory of Comparative Carcinogenesis, National Cancer Institute, FCRDC, Maryland 21702.
Zastawny
T H
TH
North
S L
SL
Riggs
C W
CW
Diwan
B A
BA
Rice
J M
JM
Dizdaroglu
M
M
D000085:Acetates / Q000008:administration & dosage / Q000633:toxicity*; D019342:Acetic Acid; D000818:Animals; D002843:Chromatin / Q000737:chemistry / Q000187:drug effects*; D004249:DNA Damage; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006868:Hydrolysis; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects / Q000648:ultrastructure; D008099:Liver / Q000187:drug effects / Q000648:ultrastructure; D008168:Lung / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344
D000085:Acetates; D002843:Chromatin; D019342:Acetic Acid