Recent findings on the metabolism of beta-hydroxyalkylnitrosamines.
beta-Hydroxynitrosamines appear to be refractory to alpha-oxidation, the common pathway of metabolism of simple dialkylnitrosamines. Some years ago, we postulated that nitrosamines bearing a hydroxyl in the beta position may be activated to alkylating agents by metabolic transformation to sulfate conjugates. Recent evidence has provided support for this hypothesis. A sulfate ester of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (NHPOPA) has been found in the urine of hamsters treated with the nitrosamine. It has also been found that inhibition of sulfotransferases inhibited the development of DNA single-strand breaks in livers of rats treated with several beta-hydroxy-nitrosamines. Alkylation of rat liver DNA in vivo by N-nitroso(2-hydroxyethyl)methylamine (NHEMA) favoured methylation over 2-hydroxyethylation by a factor of 10. The methylation reaction was inhibited by sulfotransferase inhibitors. Thus, sulfation appears to be an important pathway for activation of beta-hydroxy-nitrosamines. There are, however, other pathways, such as the oxidation of the beta-hydroxyl group to a carbonyl, which may also result in the formation of electrophilic species capable of modifying cellular macromolecules.
Michejda
C J
CJ
LBI-Basic Research Program, NCI-Frederick Cancer Research Facility, MD 21701.
Koepke
S R
SR
Kroeger-Koepke
M B
MB
Bosan
W
W
D000478:Alkylation; D000818:Animals; D004052:Diethylnitrosamine / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D006900:Hydroxylation; D008297:Male; D008745:Methylation; D009602:Nitrosamines / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000378:metabolism
D009602:Nitrosamines; D013431:Sulfates; C014129:N-nitrosodiethanolamine; D004052:Diethylnitrosamine; C012457:diisopropanolnitrosamine