The fate of [14C]streptozotocin in nicotinamide-pretreated mice: observations on pancreatic islet radioactivity and urinary N1-methyl-14C]nicotinamide-excretion.

A high labelling of the pancreatic islets was found 3 and 24 h after a diabetogenic dose of [14C]streptozotocin to mice in which the acids islet injury had been prevented by nicotinamide-pretreatment. In non-pretreated [14C]streptozotocin-injected mice, a much lower radioactivity was observed in the pancreatic islets; at 3 h and at 24 h, there was no detectable radioactivity in the islets. No evidence was found to indicate that nicotinamide-pretreatment had any marked effect on the uptake or retention of radioactivity in other tissues. N1-[methyl-14C]nicotinamide was not found in the urine of non-pretreated [14C]streptozotocin-injected mice. When the animals were pretreated with nicotinamide, N1-[methyl-14C]nicotinamide was detected in the urine, but this represented only a small fraction of the injected radioactivity and of the excreted N1-methylnicotinamide. This result does not support the hypothesis that the disturbance of the NAD-metabolism, which streptozotocin causes, is due to a methylation of nicotinamide.

Studies on the tissue-disposition and fate of N-[14C]ethyl-N-nitrosourea in mice.

The tissue-disposition and fate of N-[14C]ethyl-N-nitrosourea has been studied in mice. A large part of the injected N-[14C]ethyl-N-nitrosourea radioactivity was found to be exhaled as 14CO2. Whole-body autoradiography showed evenly distributed radioactivity in most tissues shortly after the administration of N-[14C]ethyl-N-nitrosourea which probably is due to the homogeneously distributed substance and the non-enzymatically formed ethyl-carbonium ions which have reacted with the tissues. The blood-brain barrier seemed to have a capacity to partially prevent the uptake of the substance in the central nervous system. A high radioactivity was observed in the liver, which may imply that N-[14C]ethyl-N-nitrosourea is enzymatically decomposed in this tissue. An observed labelling of kidneys may be connected with urinary excretion of radioactivity. The radioactivity in the liver and kidney decreased at later survival intervals and a distribution pattern appeared, which was characterized by a labelling of tissues with a high protein or steroid synthesis and of fat containing tissues. The distribution pattern corresponded to the one seen after the administration of [14C]acetaldehyde and is probably due to normal biosynthetic incorporation of radioactivity in the 2-carbon pool. Pretreatments with pyrazole, nialamide and diethyldithiocarbamate caused a marked inhibition of the exhalation of 14CO2 and of the incorporation of radioactivity in the liver. This effect may be directed towards the decomposition of N-[14C]ethyl-N-nitrosourea itself, but an effect on the metabolism of formed 2-carbon fragments is also possible. The incorporation of radioactivity in other tissues was not influenced by the pretreatments.

Studies on the distribution and metabolism of N-[14C]nitrosopyrrolidine in mice.

Pretreatments with pyrazole, ethanol, nialamide or diethyldithiocarbamate were found to strongly depress the exhalation of 14CO2 and the incorporation of radioactivity in the acid-insoluble fraction of the liver in mice injected with N-[14C]nitrosopyrrolidine. Whole-body autoradiography performed with hemisections of mice at -80 degrees C (to prevent evaporation of the volatile N-nitrosopyrrolidine) and with dry tape-sections (to localize the non-volatile metabolites), using pretreated and non-pretreated mice, indicated a uniform distribution of the non-metabolized N-nitrosopyrrolidine in the tissues. At the shortest survival intervals (1 and 5 min), a high level of metabolites were found in the liver, the tracheo-bronchial and nasal mucosa and Harder's gland, indicating a local formation of metabolits in these tissues. At later survival intervals (0.5--24 h) metabolites were in addition found in tissues with a rapid cell turnover and a high rate of protein synthesis and in brown fat, which probably reflects incorporation of metabolites via normal biosynthetic pathways. Autoradiography of N-[14C]nitrosopyrrolidine in mice given the substance orally resulted in distribution pictures similar to those obtained after i.v. injections.

Studies on the distribution and metabolism of 14C-dimethylnitrosamine in foetal and young mice.

In pregnant mice injected with 14C-dimethylnitrosamine, whole-body autoradiography was performed with hemisections at -80 degrees (to prevent evaporation of the volatile dimethylnitrosamine) and with dry tape sections (to localize the non-volatile metabolites). The results indicated that the non-metabolized substance passed to the foetal tissues with a uniform distribution and without formation or accumulation of non-volatile metabolites. Autoradiography in young (1-10 days old) and adult mice showed a high level of metabolites in the liver already 5 min. after the administration of 14C-dimethylnitrosamine. No metabolism of the substance could be detected at in vitro incubations of liver tissue obtained from foetuses on the last day of gestation (14CO2-production and incorporation of radioactivity in acid-insoluble macromolecules were used as metabolic indices). However, in vitro experiments with livers of 1-5 days old mice indicated a rapid increase in enzymatic activity after birth. Studies in vivo showed an increased incorporation of radioactivity in the acid-insoluble macromolecules of the liver and a decreased exhalation of 14CO2 in 10 and 14 days old mice as compared with 21 and 60 days old mice. This indicates a difference in the fate of dimethylnitrosamine in vivo between the young and older mice.