Structural relationships of pancreatic nitrosamine carcinogens

Abstract

N.m.r. spectroscopy demonstrates that N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) exists as a mixture of four isomers, A, B, C and D, the equilibrium ratios of which are 57:8:16:19, respectively, at 25 degrees C. Two of these isomers, A and B, are rotomers of the open chain conformer, while the other two, C and D, are rotomers of the ring tautomer of HPOP and are derived from A and B, respectively, via an intramolecular cyclization reaction. A syn orientation of the nitroso and carbonyl groups favors an open chain configuration (isomer A), while an anti orientation favors cyclization of the molecule (isomer D). Two forms of HPOP (I and II) which are mixtures of isomers A and C, and D and B, respectively were separated chromatographically. These two forms interconvert to each other. The first rate order constants for the interconversion reactions were determined to be 4.7 X 10(-3) and 12.8 X 10(-3)/min, respectively. During these reactions isomers A and D interconvert via the intermediate formation of isomer C. This suggests that rotomerization of C and D is thermodynamically more favorable than rotomerization of their open-chain tautomers A and B, and suggests an intramolecular interaction between the carbonyl and nitroso groups. Isomers A and D are formed during the metabolism of N-nitrosobis(2-oxopropyl)amine (BOP) and cis N-nitroso-2,6-dimethylmorpholine (NNDM), respectively, by hamster liver microsomes and NADH or NADPH. The stereo-specificity of reduction of BOP and the hydroxylation of cis NNDM results in the formation of two slowly interconvertible isomers of HPOP. This, in combination with a possible different metabolic fate of the cyclic and open tautomers of this compound, may have a significant impact on the mechanism of activation of pancreatropic nitrosamines which share HPOP as a common metabolite.

Differences in DNA-guanine alkylation between male Sprague-Dawley rats and Syrian hamsters following exposure to a single dose of pancreatic nitrosamine carcinogens

“…The above suggests that, although reduction of BOP is more effective in the liver than in any other organ in both hamsters and rats (73), the contribution of reduced metabolites in DNA alkylation in this tissue is not significant. This could be attributed to effective detoxication of HPOP via conjugation with glucuronic acid and sulfate (77), and also to effective secretion of this nitrosamine in the cirulation (13). The latter process appears to be contributing to the formation of hydroxypropyl adducts in extrahepatic tissues and especially in the kidney of the rat.…”

“…In general detoxication of HPOP is more extensive in rats than hamsters, but not as extensive as to explain the differences in its toxicity and carcinogenicity between the two species. On the other hand, differences between rats and hamsters in activating pancreatropic nitrosamine carcinogens remain unknown due to our poor understanding of the enzymology of such reactions and failure to reproduce activation of BOP and HPOP in vitro by using subcellular fractions (12,13). In this regard, a comparison of the two species in terms of their capacity to activate the above carcinogens could be better accomplished from measurements of the levels of DNA alkylation in target and nontarget tissues.…”