Metabolism and activation of the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine by isolated hepatocytes and pancreatic cells of the Syrian hamster.
The metabolism of the pancreatic carcinogen N-nitroso-bis(2-oxopropyl)amine (BOP) was studied using primary hepatocytes and acinar and duct cells isolated from Syrian hamsters. Metabolic activation of BOP was verified by detecting its conversion to CO2 covalently bound metabolites and soluble products containing the alpha-carbon of the nitrosamine. At concentrations below 0.2 mM, BOP was completely activated by hepatocytes within 60 min. At high substrate concentration (1 mM) or high cell density (5 x 10(6) cells/ml), reduction of BOP to N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine and N-nitrosobis(2-hydroxypropyl)amine contributed significantly to the metabolic profile. The conditions which favored metabolic activation of BOP were used to compare metabolism by hepatocytes and pancreatic cells. Under such conditions, the ratio of activation products formed by hepatocytes versus those formed by acinar cells was 14.5:1; the corresponding ratio for covalently bound metabolites was 19:1. Hepatocytes activated BOP 106 times more rapidly than duct cells as determined from yields of activation products or 152 times more rapidly as determined from labeling of cellular macromolecules. Acinar cells showed a higher capacity for metabolic activation than duct cells. The ratio for the yield of activation products from acinar versus duct cells was 4.3:1; the corresponding ratio for covalent binding was 5.8:1. The relatively low capacity of pancreatic cells for activation of BOP compared to hepatocytes is in agreement with the low levels of DNA binding in the pancreas compared to other organs after administration of BOP to the hamster in vivo. The observation that the ratio for total covalent binding of BOP in hepatocytes versus acinar cells was higher than that seen previously for the liver versus the pancreas in vivo is consistent with the hypothesis that alkylating agents derived from BOP reach the pancreas after formation in other organs. The liver would be the prime source for such alkylating agents.
Mangino
M M
MM
Department of Pathology, Northwestern University Medical School, Chicago, IL 60611.
Scarpelli
D G
DG
Kokkinakis
D M
DM
D000818:Animals; D001711:Biotransformation; D002245:Carbon Dioxide / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism*; D002455:Cell Division; D002478:Cells, Cultured; D006224:Cricetinae; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D009602:Nitrosamines / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology / Q000378:metabolism*; D010183:Pancreatic Ducts / Q000166:cytology / Q000378:metabolism*
D002273:Carcinogens; D009602:Nitrosamines; D002245:Carbon Dioxide; C013622:nitrosobis(2-oxopropyl)amine