Long-term persistence of DNA alkylation in hamster tissues after N-nitrosobis(2-oxopropyl)amine.
The persistence of 7- and O6-alkylation of guanine in DNA of cell nuclei of male Syrian hamster pancreas, liver, kidneys, lungs [target tissues of N-nitrosobis(2-oxopropyl)amine (BOP)] and salivary glands (nontarget tissue) was studied immunocytochemically 6 h, 1, 3, 7, 14, 28, and 56 days after a single s.c. injection of 20 mg BOP/kg. Conventional antisera raised against O6-methylguanine and imidazole-ring-opened 7-methyl-guanine were used. Persistent alkyl-specific staining was observed for up to 7 days (7-alkylguanine) or 56 days (O6-alkylguanine) in inter- and intralobular duct cells and centro-acinar cells of the pancreas, periportal hepatocytes and bile duct cells of the liver, cells of the proximal convoluted tubules of the renal cortex, and bronchiolar Clara and alveolar cells in the lungs. Both adducts disappeared from centrilobular liver cells within 1 day, from pancreatic acinar cells within 3 days, and from ducts and acini of the submandibular salivary glands within 14 days after BOP treatment. A high level of persistent O6-alkylation of guanine was related with a high tumor incidence only in case of the ductal/ductular system of the pancreas, the main target tissue of BOP-induced carcinogenesis. The relatively weak carcinogenicity of BOP in other tissues with long-term persistence of O6-alkylguanine in DNA indicates that the formation and persistence of DNA alkylation are not sufficient to account for the carcinogenic organotropism of BOP. Additional factors, such as cell proliferation, appropriate promoting stimuli and the (onco)genes critically involved, may be as important as the modification of DNA.
Bax
J
J
Division of Chemical Carcinogenesis, The Netherlands Cancer Institute, (Antoni van Leeuwenhoek Huis), Amsterdam.
Pour
P M
PM
Nagel
D L
DL
Lawson
T A
TA
Woutersen
R A
RA
Scherer
E
E
D000478:Alkylation; D000818:Animals; D002273:Carcinogens; D006224:Cricetinae; D004247:DNA / Q000378:metabolism*; D006147:Guanine / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009602:Nitrosamines / Q000378:metabolism / Q000633:toxicity*; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism
D002273:Carcinogens; D009602:Nitrosamines; D006147:Guanine; C013622:nitrosobis(2-oxopropyl)amine; D004247:DNA