Effect of dexamethasone and reserpine on brain synaptosomal phosphorylation in lithium treated rats.

Increase in brain synaptosomal protein phosphorylation after lithium treatment was unaffected by prior treatment with dexamethasone, but decreased after reserpine administration indicating the involvement of neurotransmitters in lithium induced increase in synaptosomal phosphorylation.

Biotransformation and toxicity of lindane and its metabolite hexachlorobenzene in mammals.

Lindane (gamma-hexachlorocyclohexane) is an important organochlorine pesticide used extensively for agricultural and public health purposes in India and in other developing countries. Because of its relative chemical stability and lipid solubility, it is known to enter food chains. This study was carried out in order to identify the metabolic capacity of rat-liver enzymes to transform lindane. It has been observed that lindane is made aromatic in this animal, yielding hexachlorobenzene (HCB) both in vivo and in vitro. Following the incubation of liver slices with U-14C-lindane, a significant amount of radioactivity was found to be incorporated into HCB. Although it has been reported earlier that detoxification of the pesticide occurs through dehydrochlorination reactions in mammalian species, the direct aromatization of lindane to HCB is a novel pathway and may have implications for the safety of this pesticide, since several studies have reported that HCB is carcinogenic in experimental animals. In view of the reported correlation between carcinogenicity and mutagenicity, both lindane and HCB have been tested for possible mutagenicity using the Salmonella typhimurium test system. The mutagenic response was found to be variable in different experiments.

Effects of chronic irradiation on age-related biochemical changes in mice.

Some of the biochemical indices relevant to the "free radical theory" of aging have been assessed in mice subjected to chronic low-dose whole-body irradiation. Radiation exposure results in enhanced accumulation of the lipofuscins in brain, heart, and intestine. In these animals, the degree of lipoperoxidation in liver was greatly increased, as were the free activities of acid phosphatase and cathespin, indicating damage to lysosomal membranes. The activity of SOD in brain and liver 20,000g post-mitochondrial supernatants was lower in the irradiated mice. All these changes arising from chronic whole-body irradiation are similar to those observed during aging and are effectively prevented by dietary supplementation with BHT. These observations lend considerable support to the "free radical theory" of aging.

Some aspects of corticosterone metabolism in lithium treated rats.

The effect of lithium administration on adrenal steroidogenesis has been studied in rats. An increase in plasma corticosterone (CS) levels was observed and this appears to be due to increased steroidogenesis. This effect on the adrenal is mediated via ACTH, suggesting an involvement of the pituitary adrenal axis.

Toxicity of nitrite and dimethylamine in rats.

Weanling male Wistar strain rats were administered, through the drinking water, nitrite (0.2%) and dimethylamine (DMA) (0.2%), either singly or in combination for 9 months. Some animals also received 0.5% butylated hydroxytoluene (BHT) in the diet. Nitrite, as well as DMA, caused higher in vitro lipoperoxidation, free lysosomal enzyme activities and cytosolic superoxide dismutase activity in liver. Some of these increases viz., the enzyme activities in liver, were counteracted to a significant extent in the rats receiving a dietary supplement of BHT. The results indicate that nitrite and DMA may induce toxicity through some free radical reactions and that BHT can provide some protection.

Effect of diet restriction on some biochemical parameters related to aging in mice.

The effects of chronic diet restriction in mice on some biochemical parameters related to aging have been investigated. Restriction of food intake to about one-half of the ad libitum consumption resulted in a significantly decreased growth rate immediately after weaning. In the experimental mice killed after different periods on a restricted diet up to 12 months, in vitro lipoperoxidation, the percent free activities of lysosomal enzymes and the accumulation of lipofuscins in tissues such as brain and heart were lower in comparison to those of the control animals. The superoxide dismutase activity in liver and brain did not show any consistent variations due to diet restrictions. These beneficial influences of decreased food intake on some free radical-mediated cellular damage may underlie its reported effects on longevity, in conformity with the free radical theory of aging.

Clotting abnormality in lithium treated rats.

Blood clotting was markedly influenced in rats that were given lithium, either in their diet or parenterally. The clotting of whole blood was significantly enhanced in the lithium treated rats and an assessment of [prothrombin consumption index] suggests that lithium may be exerting its effect by influencing the conversion of prothrombin to thrombin. The possible clinical significance of these findings need to be assessed.

Some biochemical parameters of ageing in relation to dietary protein.

An investigation was undertaken to study the effect of dietary protein level on some age-related biochemical processes in mice. Weanling mice were fed a laboratory diet containing protein at 6, 12 or 24% and adequate in all other nutrients, for up to 52 weeks. Although the rate of gain in body weight of the animals between 3 and 6 weeks was related to the dietary level of protein, the final body weights of mice in different groups were not significantly different. Lipid peroxidation in liver homogenate, free activities of some lysosomal enzymes of brain, liver and intestine, and the accumulation of lipofuscin pigments showed an increase with the dietary level of protein. On the other hand, the activity of superoxide dismutase in liver showed an inverse relationship to the protein level of the diet. The findings are discussed in relation to the free-radical theory of ageing.

Mechanism of liver lipid accumulation in x-irradiated rat.

The incorporation, both in vivo and in vitro, of 14C-acetate into hepatic lipids, notably the triglyceride and free fatty acid fractions, is greatly reduced following whole-body irradiation and is indicative of significantly reduced lipogenesis. Irradiation results in a several-fold increase in fatty acid oxidation, by the liver in vitro as well as in the whole animal, during the phase of active hepatic lipid accumulation. Small increases in lipoprotein lipase activity of adipose, immediately following irradiation and up to 24 hours, and the attendant marked fall in adipose lipids are suggestive of increased mobilization of peripheral lipids during the early period. However, in view of the fact that the maximum lipid accumulation occurs very much later, inflow of extra-hepatic lipid into liver does not appear to be of major etiological significance. There is three-fold experimental evidence in support of an impairment of triglyceride transport from liver being primarily responsible for the build-up of liver lipids: (I) Triton WR-1339 induced hypertriglyceridemia is totally absent in the irradiated rat during the period when liver lipids increase significantly; (II) the rate of disappearance of radioactivity from pre-labeled hepatic lipids is considerably lower in the irradiated rats; and (III) the irradiated rats show decrease in lipoproteins of liver cell-sap and of serum, the latter being more marked and a lowered synthesis of the lipoproteins, as assessed by labeling of the protein moiety.

Alterations in tissue lipids of rats subjected to whole-body X-irradiation.

Whole-body irradiation of rats at sublethal doses leads to hepatic lipid accumulation which reaches a maximum by the sixth day; this effect on lipid metabolism does not appear to be due to accompanying inanition but due to irradiation per se. The female rats show a greater and more consistent increase in liver lipids than males and this better response of the females is not abolished by prolonged administration of testosterone to these animals. An accumulation of triglycerides accounts for almost all the increases in total liver lipids, although smaller elevations in the levels of free fatty acids and cholesterol are also seen. Free fatty acids of liver show a marked decrease on the second day following irradiation. Serum lipids do not show any appreciable changes while adipose lipids progressively decrease reaching a minimum by the sixth day. Although an insufficiency of ATP may be responsible for lipid accumulation in the irradiated rat as is the case in rats treated with ethionine or orotic acid, adenine administration, which prevents fatty infiltration due to these chemical agents, does not protect against the radiation-induced increase in liver triglycerides.

Evaluation of freshly irradiated wheat for dominant lethal mutations in Wistar rats.

Three independent, serially performed experiments involving acute and chronic feeding of freshly irradiated wheat (75 krad, gamma-irradiation) were carried out in Wistar rats. In the first experiment groups of 10 males were given wheat for 1 week; irradiated wheat was consumed by the animals within 24 h or irradiation. In the other two experiments feeding of males was continued for 6 (10 males per group) and 12 (13 males per group) weeks, respectively, and the irradiated wheat was fed within 7 days of irradiation. At the end of each treatment period each male was paired with 3 females for 7 days and sequentially at weekly intervals for 5 or 8 weeks. Females were killed and examined for live and dead implantations and corpora lutea. There were no differences between groups with regard to fertility nor was there any inter-group differences as regards pre- and post-implantation losses whether the rats were fed irradiated or non-irradiated wheat. This suggested that even feeding of freshly irradiated wheat does not induce any dominant lethal mutations in rats.

Studies on mutagenicity of irradiated sugar solutions in Salmonella typhimurium.

Irradiated sugar solutions are mutagenic towards Salmonella typhimurium, the effect being dose-dependent up to 2.0 Mrad. At all doses, ribose solution exhibited greater mutagenicity than did sucrose solution. The mutagenic effect was observed only in dividing cells and appears to be directly related to the growth rate. A larger proportion of revertants was observed after incubation with irradiated sugar solution for a period of 4 h than for 24 h. Irradiation of the sugar solutions in the frozen conditions was effective in completely preventing the development of mutagenic potential. Post-irradiation storage of the sugar solutions for a prolonged period (25 weeks) also minimized their mutagenic effect. The irradiated sugar solutions gave rise to both missense and frame-shift (additon as well as deletion) types of mutation; ribose was more effective in inducing the latter type. The irradiated sugar solutions failed to show a mutagenic response in the host-mediated assay with mice as the mammalian host.

Actinomycin D-induced enhancement of ubiquinone biosynthesis in rat.

Administration of actinomycin D to fasted rats induces an enhancement of the labeling of hepatic ubiquinone by [2-14C] acetate both in vivo and in vitro. The incorporation of [2-14C] mevalonate into ubiquinone is also increased, although to a significantly lesser extent; this, however, presumably results from greater uptake of the labeled precursor by liver of drug-treated rats. The drug-administered animals show increased activity of liver microsomal mevalonate: NADP oxidoreductase, the rate-limiting enzyme in isoprenoid biogenesis. The incorporation of [u-14C] benzoic acid and CH3-[14C] methionine into ubiquinone in liver slices, however, reveals a decrease in actinomycin D administered rats. This appears to be due to a specific inhibition of the pathway leading to the benzoquinone moiety of ubiquinone and not to an increase in the pool-size of the precursors. The stimulatory effect of the drug on ubiquinone biosynthesis is also observable in cholesterol-fed rats. The actinomycin D-induced increase in ubiquinone biosynthesis is dependent on new protein synthesis since the effect is abolished by treating the animals with either cycloheximide or puromycin.