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.