D. D. Feller

The influence of starvation upon hepatic drug metabolism in rats, mice, and guinea pigs.

Summary Male rats, mice, and guinea pigs were starved for 1, 2, or 3 days; and the metabolism of ethylmorphine, p-nitroanisole, and aniline was studied. The metabolism of aniline was stimulated by starvation in mice, rats, and guinea pigs; the metabolism of p-nitroanisole was stimulated only in mice and rats; and the metabolism of ethylmorphine was stimulated by starvation only in mice. The results suggest that the oxidative enzyme systems studied are not interdependent, and the pathways studied appear to be species dependent.

Effects of pentobarbital on plasma glucose and free fatty acids in the rat.

Summary Hyperglycemia and hypolipemia were observed in rats after the injection of sodium pentobarbital (Nembutal). The observed changes were independent of whether the blood was collected by decapitation or by needle puncture of the aorta. The hyperglycemic response was caused by two factors, the stress of the injection per se and the pharmacological action of the drug. Hyperlipemia was observed at 5 min postinjection; however, pentobarbital decreased plasma free fatty acids by 15 min postinjection. Both the hyperglycemia and hypolipemia responses were dose dependent.

Mitotic response to various dietary conditions in the normal and regenerating rat liver.

Summary Rats were subjected to diets high in carbohydrate, protein, or fat for 7 days or to a 24-hr fast. Some of these rats were partially hepatectomized and the mitotic activity of the regenerating liver was measured either 20 or 24 hr postoperatively. The level of mitotic activity of the intact liver from the unoperated rats were also determined. The unoperated rats fed the high protein diet showed an increase in the resting mitotic activity, while those fed the high fat diet showed a decrease when these rats were compared to control rats fed a normal diet. Caloric restriction and food deprivation (24-hr fast) also caused a decrease in the resting mitotic activity. The partially hepatectomized rats fed the high protein and high fat diets or fasted for 24 hr showed a reduced mitotic activity during the periods studied, whereas caloric restriction had no effect. The high carbohydrate diet had no effect on the mitotic activity of either the intact or regenerating liver.

Effects of Hyperoxia and Hypoxia on Mitosis in the Normal and Regenerating Rat Liver

Summary Unoperated and partially hepatectomized rats were exposed to 100% O2 at 760, 258, and 191 mm Hg for various time periods up to 34 hr. No change in mitotic activity was noted in these animals when compared to appropriate controls. Similar groups of rats were exposed to a hypoxic condition (air, 380 mm Hg) for the same time periods as above. The partially hepatectomized group showed a delay in the initiation of mitosis, while the unoperated group showed a reduction in mitotic activity due to the hypoxic environment.

CHEMICAL AND METABOLIC CHANGES OF HEPATIC LIPIDS FROM RATS EXPOSED TO CHRONIC RADIAL ACCELERATION.

Summary From weaning until 1 year of age female Sprague-Dawley rats were centrifuged at 3.6 and 4.7 g. Liver slices of these rats were incubated with C14-labeled acetate and its incorporation into fatty acids, nonsaponifiable lipids, and CO2 was measured. When compared with tissue from control rats, liver slices of centrifuged rats exposed to 4.7 g showed an increased formation of C14-nonsaponifiable lipids. Comparable changes were not observed in rats exposed to 3.6 g. No significant alteration was noted for incorporation of acetate into fatty acids or CO2. The total lipid content of the liver was decreased significantly in rats exposed to 4.7 g. The response evoked from long-term exposure affected synthesis of nonsaponifiable lipids whereas short-term exposure affected fatty acid synthesis.

A common modality of action of simulated space stresses on the oxidative metabolism of ethylmorphine, aniline and p-nitroanisole by male rat liver

Abstract Male Simonson rats were exposed to high gravity (4.15 g for 7 days), cold (4°C for 4 days), starvation (no food for 2 days) or hypobaric-hyperoxia (350 mm Hg-100% O 2 for 4 days). High gravity, cold and starvation elicited similar qualitative responses, including a decreased rate in body weight gain, increased metabolism of aniline and p -nitroanisole and no consistent pattern of change in the metabolism of ethylmorphine. Cold and starvation increased the amount of hepatic cytochrome P-450, while hypobaric-hyperoxia caused no change in any of the parameters measured. When 1% acetone was given to rats in their drinking water, the effects on drug metabolism were similar to those produced by food restriction in that the metabolism of aniline and p -nitroanisole was increased, and the metabolism of ethylmorphine not changed. Acetone and also γ-hydroxybutyric acid produced type I binding spectra in the 9000 g supernatant fraction. The evidence suggests that ketone bodies may inhibit microsomal enzyme reactions involving type I substrates. Ketone bodies have also been reported to inhibit fatty acid synthetase that requires NADPH; increased metabolism of type II substrates may occur because of increased availability of NADPH.

Blood glucose and corticosterone changes accompanying altered lipid metabolism induced by exposure to acceleration stress.

Summary Fasted, male, Sprague-Dawley rats were exposed to 4.7 g for periods of time up to 24 hours. Plasma glucose, plasma corticosterone, liver lipids, and incorporation of acetate-1-C14 into fatty acids in liver slices were followed in rats exposed for periods of 1–24 hours. Plasma glucose and plasma corticosterone curves were bimodal showing an early maximum during the first 3 hours of exposure and rising after 5 hours through the 24-hour study. During the second rise the greatest changes in lipid metabolism were noted as a decrease in liver lipid and an increase in fatty acid synthesis. The responses evoked by the stress were abolished by hypophysectomy or adrenalectomy. It is concluded that changes in fat metabolism induced by acceleration stress were mediated, in part, by changes in levels of circulating glucose, corticosterone, or the interaction of both.

Conversion of Glucose-14C(UL) to 14CO2, 14C-Glycogen, and 14C-Fatty Acids in the Partially Hepatectomized Rat

Summary Partially hepatectomized (67%) rats and sham-operated controls were injected with glucose-14C(UL) at various times postoperative from 1 hr to 1 week and the expired 14CO2 and CO2 was measured for 3 hr. At the end of the radiorespirometry procedure, plasma free fatty acids, glucose, cholesterol, and 14C-lipids were determined. Fatty acids, 14C-fatty acids, nonsaponified 14C-lipids, glycogen, and 14C-glycogen were determined in liver. Glycogen and 14C-glycogen were also determined in muscle. Upon partial hepatectomy plasma free fatty acids increased while glucose and cholesterol decreased. The cumulative percentage of recovery of 14CO2 decreased in the partially hepatectomized rat during the first hour of the radiorespirometry period. However, no significant difference between the partially hepatectomized rats and the sham-operated controls was noted at the end of the 3-hr radiorespirometry period. The specific activity of the expired CO2 was increased in the partially hepatectomized rats because of their decreased CO2 production. The specific activity of muscle glycogen was decreased in the partially hepatectomized rats while liver glycogen showed an increase which is interpreted to mean the turnover of muscle glycogen is decreased while the turnover of liver glycogen is increased. The recovery of liver 14C-fatty acids and nonsaponified 14C-lipid was decreased, indicating that a decreased conversion of glucose to acetyl CoA occurs in the partially hepatectomized rat. The effect of isotopic dilution resulting from a difference in plasma glucose levels between the two groups of rats is discussed.

Conversion of Acetate-2-14 to 14CO2 and 14C-Fatty Acids in the Partially Hepatectomized Rat

Summary Partially hepatectomized (67%) rats were injected with acetate-2-14C at various times postoperative and the expired 14CO2 and CO2 measured for 3 hr. Liver 14C-nonsaponifiable lipids, 14C-fatty acids, and total fatty acid content were determined. Plasma triglycerides, phospholipids, free fatty acids, and 14C-lipids were determined. The recovery of 14CO2 showed no significant difference from sham-operated controls except during the 72-75-hr postoperative period when an increased excretion was noted. The specific activity of the expired CO2 of the partially hepatectomized rat was increased as a result of a lower CO2 production. The lower CO2 production was attributed to an increased lipid oxidation by the partially hepatectomized rat. The appearance of 14C as plasma lipids was proportional to the mass of the regenerating liver. Recovery of 14C as liver fatty acids was comparable to shamoperated and nonoperated control values. The results suggest that, in addition to deposition via transport, the fatty acid content of the regenerating liver is also increased by synthesis in situ during the premitotic as well as the mitotic phase.

Increased partial pressures of oxygen at normal barometric pressure on lipogenesis in rat tissues.

Summary Male rats, fed ad libitum, were exposed to 30% and 47% oxygen environments (balance, N2) at 1 atm for periods of time varying from 1 to 4 days. The rats exposed to increased oxygen tensions for 3 or 4 days gained more weight than controls. Fatty acid contents of liver and adipose tissue of the experimental group at 4 days of exposure were higher than the fatty acid contents found in these tissues for the control group. Conversion of acetate to fatty acids was found to be significantly higher in liver and adipose tissue of oxygen enriched animals. The conclusion is drawn that these findings are the result solely of an increase in alveolar oxygen tension.