Time Course of Change in Glutathione S-Transferase Positive Foci and Ornithine Decarboxylase Activity after Cessation of Long-term Alcohol Administration in Rats.
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In our previous experiments, we showed that cessation of long-term alcohol administration enhances hepatocarcinogenesis in the rat. In the present study, we examined the time course of hepatocarcinogenesis induced by diethylnitrosamine (DEN) after cessation of alcohol using numbers and areas of glutathione S transferase placental form (GST-P)-positive foci and the activity of ornithine decarboxylase (ODC) in males of the Wistar strain. Fifty six rats were given a single i.p. injection of DEN (200 mg/kg body weight), maintained on basal solid diet for two weeks, then maintained on liquid diet in which 36% of total calories were provided by ethanol (Al diet) for 12 weeks, and then eight rats were killed. The remaining rats were divided into 6 groups. Three alcohol cessation groups were maintained on control liquid diet (C diet) instead of Al diet for 3, 6 and 12 weeks, respectively. The others, as reference groups were maintained on the Al diet continuously for the same periods, respectively. The numbers of GST-P-positive foci per unit area of the liver were not markedly changed after cessation of alcohol. However, their areas were increased with time, so that values in the alcohol cessation groups at 3 and 12 weeks were significantly higher than those in the reference groups at the same points, respectively. Furthermore, ODC activity was significantly elevated in the alcohol cessation groups at 3 and 6 weeks compared to reference groups, but not at 12 weeks when reduction was rather observed. These results suggest that cessation of long-term alcohol administration enhances hepatocarcinogenesis and this effect may be closely related to activation of cell proliferation due to the interruption of alcohol insult.Keywords:
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Basal (medicine)
Liquid diet
Glutathione S-transferase
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In our previous experiments, we showed that cessation of long-term alcohol administration enhances hepatocarcinogenesis in the rat. In the present study, we examined the time course of hepatocarcinogenesis induced by diethylnitrosamine (DEN) after cessation of alcohol using numbers and areas of glutathione S transferase placental form (GST-P)-positive foci and the activity of ornithine decarboxylase (ODC) in males of the Wistar strain. Fifty six rats were given a single i.p. injection of DEN (200 mg/kg body weight), maintained on basal solid diet for two weeks, then maintained on liquid diet in which 36% of total calories were provided by ethanol (Al diet) for 12 weeks, and then eight rats were killed. The remaining rats were divided into 6 groups. Three alcohol cessation groups were maintained on control liquid diet (C diet) instead of Al diet for 3, 6 and 12 weeks, respectively. The others, as reference groups were maintained on the Al diet continuously for the same periods, respectively. The numbers of GST-P-positive foci per unit area of the liver were not markedly changed after cessation of alcohol. However, their areas were increased with time, so that values in the alcohol cessation groups at 3 and 12 weeks were significantly higher than those in the reference groups at the same points, respectively. Furthermore, ODC activity was significantly elevated in the alcohol cessation groups at 3 and 6 weeks compared to reference groups, but not at 12 weeks when reduction was rather observed. These results suggest that cessation of long-term alcohol administration enhances hepatocarcinogenesis and this effect may be closely related to activation of cell proliferation due to the interruption of alcohol insult.
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The activity of ornithine decarboxylase, the rate-controlling enzyme in polyamine biosynthesis, was determined in tissues of normal control rats and rats made diabetic with streptozotocin. In untreated diabetic rats fed ad libitum, ornithine decarboxylase activity was markedly diminished in liver, skeletal muscle, heart and thymus. Ornithine decarboxylase was not diminished in a comparable group of diabetic rats maintained on insulin. Starvation for 48h decreased ornithine decarboxylase activity to very low values in tissues of both normal and diabetic rats. In the normal group, refeeding caused a biphasic increase in liver ornithine decarboxylase; there was a 20-fold increase in activity at 3h followed by a decrease in activity, and a second peak between 9 and 24h. Increases in ornithine decarboxylase in skeletal muscle, heart and thymus were not evident until after 24–48h of refeeding, and only a single increase occurred. The increase in liver ornithine decarboxylase in diabetic rats was greater than in normal rats after 3h of refeeding, but there was no second peak. In peripheral tissues, the increase in ornithine decarboxylase with refeeding was diminished. Skeletal-muscle ornithine decarboxylase is induced more rapidly when meal-fed rats are refed after a period without food. Refeeding these rats after a 48h period without food caused a 5-fold increase in ornithine decarboxylase in skeletal muscle at 3h in control rats but failed to increase activity in diabetic rats. When insulin was administered alone or together with food to the diabetic rats, muscle ornithine decarboxylase increased to activities even higher than in the refed controls. In conclusion, these findings indicate that the regulation of ornithine decarboxylase in many tissues is grossly impaired in diabetes and starvation. They also suggest that polyamine formation in vivo is an integral component of the growth-promoting effect of insulin or some factor dependent on insulin.
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The regulation of the activity of the renal enzyme omithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17) was examined in the rat. In the intact animal adapted to a light/dark cycle of 14 hours and 10 hours, respectively, the level of renal omithine decarboxylase activity was rhythmical and paralleled the diurnal rhythm in plasma corticosteroid concentration. Renal omithine decarboxylase activity and plasma corticosterone were highest during the early hours of darkness and lowest during the hours of light. Following hypophysectomy, the level of renal omithine decarboxylase activity declined rapidly and remained low and without a demonstrable diurnal rhythm. When pituitary hormone levels were temporarily restored in the hypophysectomized rat by the injection of pituitary extract, renal ornithine decarboxylase activity increased rapidly, reached a peak within 8 hours, and returned toward pre-injection levels by 12 hours. Exogenous growth hormone, ACTH and cortisol each increased renal omithine decarboxylase activity in the hypophysectomized rat, with the highest levels of activity being achieved with growth hormone. Other pituitary hormones (FSH, LH, TSH and prolactin) were ineffective. After bilateral adrenalectomy, renal omithine decarboxylase activity retained a rhythmical pattern similar to that observed in the intact rat, but the levels were increased. Growth hormone and cortisol increased renal ornithine decarboxylase activity in the adrenalectomized-hypophysectomized animal to the same extent as in the hypophysectomized animal, but ACTH was almost totally ineffective. These data suggest that the pituitary plays a major role in theregulation of renal ornithine decarboxylase activity in the rat, primarily through the rhythmical secretion of growth hormone and ACTH.(Endocrinology98: 123,1976)
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In mice deprived of water, renal ornithine decarboxylase (ODC) activity declined rapidly and remained depressed for up to 3 days. Dehydration, via substitution of 2% NaCl for drinking water, produced an initial decline in kidney enzyme activity followed by a continuing increase throughout a 4-day treatment period. Arginine vasopressin (AVP) injection caused a rapid, transient elevation in ODC activity in the kidney. Adrenalectomy had no effect on basal ODC activity in the kidney, whereas propylthiouracil treatment and gonadectomy (acute) caused a marked reduction in enzyme activity. The renal ODC response to AVP injection was blunted in each of these endocrinologically altered mice. Basal ODC levels were normal in mice 120 days postorchidectomy, as was the response to AVP. These results indicate that some of the effects of dehydration on renal ODC may be due to mechanisms other than those induced by the normal secretory products of the posterior pituitary.
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Hepatic glutathione S-transferase activities were determined with the substrates 1,2-dichloro-4-nitrobenzene and 1-chloro-2,4-dinitrobenzene. Sexual differentiation of glutathione S-transferase activities is not evident during the prepubertal period, but glutathione conjugation with 1,2-dichloro-4-nitrobenzene is 2–3-fold greater in adult males than in females. Glutathione conjugation with 1-chloro-2,4-dinitrobenzene is slightly higher in adult males than adult females. No change in activity was observed after postpubertal gonadectomy of males or females. Neonatal castration of males results in a significant decrease in glutathione conjugation with 1,2-dichloro-4-nitrobenzene. Hypophysectomy, or hypophysectomy followed by gonadectomy did result in significantly higher glutathione S-transferase activities in both sexes. These increases can be reversed by implanting an adult male or female pituitary or four prepubertal pituitaries under the kidney capsule. Postpubertal sexual differentiation of glutathione S-transferase activities is neither dependent on pituitary sexual differentiation nor pituitary maturation. Prolactin concentrations are inversely related to glutathione S-transferase activities in hypophysectomized rats with or without ectopic pituitaries. Somatotropin exogenously administered to hypophysectomized rats results in decreased glutathione S-transferase activities, whereas prolactin has no effect. Adult male rats treated neonatally with monosodium l-glutamate to induce arcuate nucleus lesions of the hypothalamus have decreased glutathione S-transferase activities towards 1,2-dichloro-4-nitrobenzene and decreased somatotropin concentrations. Our experiments suggests that sexual differentiation of hepatic glutathione S-transferase is a result of a hypothalamic inhibiting factor in the male (absent in the female). This postpubertally expressed inhibiting factor acts on the pituitary to prevent secretion of a pituitary inhibiting factor (autonomously secreted by the female), resulting in higher glutathione S-transferase activities in the adult male than the adult female.
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In this study, the catecholamine levels of the myocardium in both well-nourished and malnourished alcohol-fed rats were examined. Alcohol has been administered to rats for 16 weeks. Rats fed a diet containing alcohol corresponding to 40% of total caloric intake and inadequate amounts of calories and nutrients showed increased levels of noradrenaline in the heart whereas the controls did not (alcohol-fed rats, 0.888 ± 0.050 μg/g wet tissue weight; controls, 0.668 ± 0.025 μg/g). In addition an increase in heart ratio (gram heart weight/kilogram body weight) could be also observed (alcohol-fed rats, 3.17 ± 0.10; controls, 2.65 ± 0.05). However, between well-nourished rats fed alcohol as 35% of the caloric intake and pair-fed controls there were no differences in catecholamine concentration (alcohol-fed rats, 0.729 ± 0.068 μg/g; pair-fed controls, 0.738 ± 0.069) and heart ratio (alcohol-fed rats, 2.84 ± 0.15; pair-fed controls, 2.75 ± 0.09). From these results, it is concluded that chronic consumption of alcohol induces an increase in myocardium noradrenaline concentration and heart hypertrophy only when it is associated with malnutrition, i.e., alcohol by itself does not alter either of these parameters. Moreover, it can be speculated that continued exposure to high levels of catecholamine may play a role in the development of myocardial hypertrophy.
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Prolonged alcohol consumption (5 months) concomitant with adequate nutrition was found to impair the acquisition and performance of timing behavior. Alcohol was administered in the form of a liquid diet containing 35 percent ethanol-derived calories as the only source of fluid and calories. One control group received the identical liquid diet with isocaloric substitution of sucrose for ethanol, and another control group received laboratory chow and water without restriction. Thirty days after ethanol was discontinued in the diet, the alcohol-consuming rats were severely impaired in acquisition and performance of timing behavior as compared to controls.
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