Stimulation of Diethylnitrosamine Metabolism Reduces Its General Toxic and Hepatocarcinogenic Effects.

The general toxic and hepatocarcinogenic effects of diethylnitrosamine after stimulation of its metabolism with 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP) were studied. The hydroxylating activity of liver microsomes of C57Bl/6Mv mice towards p-nitrophenol increased more than 4-fold 3 days after injection of TCPOBOP. Injection of diethylnitrosamine 3 days after TCPOBOP caused a lesser body weight loss and decrease of food consumption in C57Bl/6Mv mice than in response to diethylnitrosamine without preinduction. Injection of diethylnitrosamine to suckling ICR mice after TCPOBOP induction of cytochrome P450 2e1 activity led to development of 2-fold lesser number of tumors and pretumorous nodes in the liver in comparison with animals injected with diethylnitrosamine without induction. These data indicated that metabolism stimulation reduced the general toxic and hepatocarcinogenic effects of diethylnitrosamine.

Suppression of sulfoconjugation reduces the protective effect of ortho-aminoazotoluene on hepatocarcinogenesis induced by diethylnitrosamine in mice.

The effects of ortho-aminoazotoluene on carcinogenic activity of diethylnitrosamine were studied in CBA and ICR mice. Injection of ortho-aminoazotoluene before and after diethylnitrosamine led to a significant reduction of its anticarcinogenic effect, judging from significantly lower level of liver tumors. Pentachlorophenol, inhibitor of sulfotransferase (catalyzing the terminal stage of ortho-aminoazotoluene metabolic activity), stimulated its carcinogenic effect on mouse liver. On the other hand, pentachlorophenol reduced the protective effect of ortho-aminoazotoluene on diethylnitrosamine-induced hepatocarcinogenesis in mice. Presumably, the carcinogenic and anticarcinogenic effects of ortho-aminoazotoluene were realized by its initial form or intermediate (non-sulfated) metabolites.

Effects of administration of sodium glutamate during the neonatal period on behavior and blood corticosterone levels in male mice.

Treatment of male DBA/2 mice with sodium glutamate (4 mg/g) on postnatal days 1, 3, 5, 7, and 9 induced reductions in the numbers of square crossings, vertical rearings, excursions to the center, and the time spent in the center in adulthood, as compared with a group of males given physiological saline at the same times. These measures showed no change as compared with intact animals. In the light-dark test, the time spent by mice in the light sector was greater after administration of sodium glutamate than after administration of physiological saline but did not differ from that in intact animals. In the acoustic startle reflex test, sodium glutamate decreased startle amplitude but had no effect on the magnitude of prestimulus inhibition. Sexual motivation in males decreased after sodium glutamate, physiological saline producing a tendency to decreased sexual motivation. Neonatal administration of sodium glutamate increased basal blood corticosterone in adult males by a factor of 4, while physiological saline had no effect on this measure. These results lead to the conclusion that neonatal administration of sodium glutamate decreases motor and investigative activity, anxiety, and sexual motivation in adult male mice and increases basal corticosterone. Physiological saline increased all these parameters apart from sexual motivation, though this was not associated with changes in basal corticosterone.

Promoting effect of o-aminoazotoluene on hepatocarcinogenesis is accompanied by the increase in inflammatory and proliferative processes in liver tissue and decrease in the concentration of free thyroxin in the blood.

o-Aminoazotoluene in noncarcinogenic doses promoted the development of liver tumors in female ICR mice induced by administration of diethylnitrosamine during early ontogeny. Severe inflammatory infiltration and proliferation of oval cells were found in liver tissue of these animals. The concentration of free thyroxin decreased in the blood. Our results supplement published data that promoters of hepatocarcinogenesis inhibit thyroid function.

Effect of neonatal injection of sodium glutamate and diethylnitrosamine on hepatocarcinogenesis, reproductive and adrenocortical systems of male mice.

Neonatal injection of sodium glutamate before injection of diethylnitrosamine decreased the number of tumor nodes in the liver of male mice, decreased the weight of the testes and adrenals and blood level of testosterone (but increased blood level of corticosterone), impaired recovery of diethylnitrosamine-disturbed sexual motivation in half of males. Anticarcinogenic effect of sodium glutamate is explained by feminization of males under its effect.

Relationship between high sensitivity of suckling mice to hepatocarcinogenic and antiglucocorticoid effects of o-aminoazotoluene and diethylnitrosamine.

Suckling mice were more sensitive to the hepatocarcinogenic effect of various carcinogens compared to adult animals. After treatment with o-aminoazotoluene and diethylnitrosamine HNF3-DNA-binding capacity and glucocorticoid-induced liver tyrosine aminotransferase activity in suckling mice decreased more significantly than in adult animals.

Effect of liver macrophage depression on the development of liver metastases of HA-1 tumor in mice.

Gadolinium chloride (5 mg/kg) administered to mice 24 h before intravenous transplantation of HA-1 hepatoma cells decreased the volume density of tumor implants in the liver, reduced the intensity of degenerative and necrotic changes developing under the effect of growing tumor metastases, and prolonged the life span of tumor-bearing mice. Development of metastases was not associated with changes in cathepsin B activity in the liver, while activity of cathepsin L decreased only during the early period (4 days) after injection of gadolinium chloride. Injection of gadolinium chloride led to labilization of liver cell lysosomes because of overload with gadolinium chloride particles. The positive effect of gadolinium chloride was probably associated with depression of liver macrophages at the stage of tumor cell invasion and with subsequent migration of monocytes/macrophages preventing the growth of formed metastatic nodes in the liver.

Predisposition to alcoholism, tryptophan oxygenase activity, and structure of intron 6 in the corresponding gene of C57BL/6J, CC57BR/Mv, and BALB/cJ mice.

Crossbred CC57BR/Mv mice inherited tryptophan oxygenase gene and predisposition to alcohol consumption from parent BALB/c and C57BL mice, respectively. In CC57BR/Mv mice no relationships were found between alcohol consumption, tryptophan oxygenase activity, and single nucleotide substitutions in intron 6 of the TDO2 gene associated with predisposition to alcoholism in humans.

Potentiation of antitumor effects of cisplatin by tumor necrosis factor-beta.

Recombinant tumor necrosis factor-beta potentiated the inhibitory effect of cisplatin on intramuscularly transplanted GA-1 tumor and liver metastasis in mice. The antitumor effect was related to cytotoxic and cytostatic activities of the test preparations rather than to initiation of apoptosis.

Elevated basal activity of tryptophan oxygenase in alcohol-preferring C57BL mice.

Tryptophan oxygenase activity in alcohol-preferring C57Bl mice and control CBA and DBA/2 mice was studied under nonstressful conditions and after glucocorticoid-induced stress. Elevated basal tryptophan oxygenase activity in C57Bl mice is probably responsible for reduced brain content of tryptophan and serotonin associated with alcohol preference.