Effect of plasma and carboxylesterase on the stability, mutagenicity, and DNA cross-linking activity of some direct-acting N-nitroso compounds.
The effects of mouse plasma, human plasma, and purified porcine liver carboxylesterase on nitrosourea, nitrosamide, and nitrosocarbamate chemical stability, mutagenicity, and DNA cross-linking activity were compared. These three classes of N-nitroso compounds are chemically similar but displayed different biological activities and were affected differently by plasma and carboxylesterase. Nitrosourea stability as well as mutagenicity and DNA cross-linking activity were affected negligibly by esterase or plasma. In contrast, nitrosamide and nitrosocarbamate stability, mutagenicity, and DNA cross-linking activity were rapidly decreased in the presence of plasma or carboxylesterase. For example, chemical half-lives were from 10- to 20-fold shorter for the nitrosamides and nitrosocarbamates in the presence of 5% mouse plasma. Similar decreases were seen for mutagenicity and DNA cross-linking activity. Preliminary studies indicated one active plasma component to be an enzyme, possibly an esterase. Additional factors such as sulfhydryls may also participate. Whereas some nitrosoureas are active antitumor agents, the lack of antitumor activity for analogous nitrosamides and nitrosocarbamates may reside predominantly in their rapid in vivo inactivation. These results may help to account for the high in vitro mutagenicity as compared with the low in vivo activities of nitrosamides and nitrosocarbamates.
D000818:Animals; D001769:Blood; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D008099:Liver / Q000201:enzymology; D051379:Mice; D009602:Nitrosamines / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology*; D009607:Nitrosourea Compounds / Q000494:pharmacology; D013552:Swine
D009602:Nitrosamines; D009603:Nitroso Compounds; D009607:Nitrosourea Compounds; C013621:nitrosamides; C036492:nitrosocarbamic acid; D004247:DNA; D002265:Carboxylic Ester Hydrolases