Carcinogenesis by nitrosobis-(2-oxopropyl)amine labeled with deuterium and by nitroso-2-hydroxypropyl-2-oxopropylamine in rats and hamsters.
The effects of the labeling with deuterium of the alpha-methylene groups of the carcinogen nitrosobis-(2-oxopropyl)amine (NBOP) on its carcinogenic effectiveness in rats and hamsters have been studied. The greater strength of the C-D bond compared with the C-H bond often leads to slower metabolism and lesser carcinogenic activity. When NBOP and NBOP-d4 were given to male and female rats in drinking water at equimolar doses, the mortality rate from tumors was lower in the rats given the deuterium-labeled compound, although the results were statistically significant (P = 0.012) only in males. The incidences of tumors of several groups was similar for NBOP and NBOP-d4, but there was a marked difference between males and females, females having a high incidence of liver tumors, and males very few. When NBOP and NBOP-d4 were given by gavage to rats or Syrian hamsters at identical doses there was no difference in rate of mortality from tumors, or in the pattern of tumors induced by either compound. In rats, both compounds were given at two dose rates, and in neither was a difference seen. To complement the studies with NBOP, a normal reduction product formed metabolically in vivo, nitroso-(2-hydroxypropyl) (2-oxopropyl)amine (NHPOP) was administered to rats in drinking water at the same dose rate. In male rats, the mortality rate was lower with NHPOP than with NBOP, while with female rats the opposite was the case (P less than 0.01 in both cases) and there was little difference in the pattern of tumors induced in either sex. NHPOP appears to have a quite distinct carcinogenic effect from NBOP, suggesting that the metabolic conversion of one to the other does not play a large role. The weak deuterium-isotope effect of NBOP-d4 given to rats in drinking water, but not detected in rats or hamsters treated by gavage, suggests that alpha-oxidation of NBOP is not likely to be a rate-limiting step in carcinogenesis by NBOP.
Lijinsky
W
W
NCI-Frederick Cancer Research Facility, BRI-Basic Research Program, MD 21701.
Saavedra
J E
JE
Kovatch
R M
RM
D000818:Animals; D006224:Cricetinae; D003903:Deuterium; D005260:Female; D007553:Isotope Labeling; D008297:Male; D008647:Mesocricetus; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism / Q000633:toxicity*; D010084:Oxidation-Reduction; D051381:Rats; D012737:Sex Factors
D009602:Nitrosamines; C013622:nitrosobis(2-oxopropyl)amine; C013624:N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine; D003903:Deuterium