Hepatic ATP Levels Research Articles

Phase-related changes in tissue energy reserves during hemorrhagic shock

In view of the well-known fact that the liver is more sensitive to ischemia than skeletal muscle, it was the purpose of the present study to determine the relationship between the hemorrhage-induced changes in plasma glucose and lactate concentrations and the status of the energy reserves of these two tissues. Sprague-Dawley rats were bled to a constant mean arterial blood pressure of 40 mm Hg and held there by removal or reinfusion of blood. The stages of shock defined on the basis of the net blood loss were (1) early compensatory, (2) maximal compensatory, (3) early decompensatory, and (4) late decompensatory phases. The results showed a depletion of hepatic ATP levels which occurred between the early compensatory and maximal compensatory phases of shock, coincident with the most dramatic increases in plasma glucose and lactate seen during the shock protocol. Hepatic ATP levels fell no further through the decompensatory phases of shock while plasma glucose declined to hypoglycemic levels and plasma lactate was maintained at the same high level attained at the maximal compensatory phase. Since hepatic sources of glucose were exhausted by the maximal compensatory phase and hepatic energy stores were depleted to a point which precludes significant gluconeogenesis, the large increase in plasma lactate was probably largely due to loss of the hepatic “sink” for lactate during this phase of shock. In contrast to the liver, soleus muscle showed no change in the levels of glycogen, ATP, CrP, free creatine, or total creatine compared to time-matched controls in any phase of hemorrhagic shock suggesting the absence of significant muscle ischemia. The possibility that red skeletal muscle may act as a “sink” for lactate is considered.

The effects of torpor on adenosine triphosphate storage in the California pocket mouse, Perognathus californicus

1. 1. ATP levels of cardiac and hepatic tissues were determined in Perognathus californicus and Mus musculus in various metabolic and thermal states. 2. 2. Mus showed an increased cardiac ATP level in cold-exposed individuals, While there were no differences between ATP levels in control, cold-exposed and hypothermie Perognathus. 3. 3. Hepatic ATP levels were similar in both species in control and cold-exposed groups, while hypothermie Perognathus had significantly higher levels. 4. 4. The elevation of hepatic ATP during hypothermia has also been observed in long-term hibernators and may be of benefit during the arousal process in Perognathus.

Derangement of hepatic energy metabolism in lead-sensitized endotoxicosis.

Lead-sensitized endotoxicosis was investigated in rats in terms of hepatic energy metabolism. Lead acetate (Ld, 20 mg/kg BW) or endotoxin (Etx, 4 mg/kg BW) caused no deaths within 48 h. Ld plus Etx resulted in a lethality of 50 and 100% within 6 and 12 h respectively. Etx or Ld alone caused a slight but significant decrease in the hepatic tissue levels of total adenine nucleotides and/or ATP at 3 and 6 h after the application. The energy charge potential (ECP) remained normal. The ketone bodies acetoacetate and beta-hydroxybutyrate and the ratio AcAc/beta-OHB as well as the mitochondrial oxidative phosphorylation tended to increase; the hepatic tissue levels of pyruvate and lactate were increased after 3 h, indicative of an accelerated glycolysis. These alterations were no longer detectable after 6 h. In lead-sensitized endotoxemia (Ld + Etx), the total adenine nucleotides and ATP of the liver tissue decreased significantly to 84% (86%) and 71% (52%) of the controls within 3 and 6 h respectively, and the ECP had decreased from 0.865 to 0.684 at 6 h. The ketone bodies were increased, while the ratio AcAc/beta-OHB was significantly decreased at 6 h. The hepatic tissue lactate remained elevated. The mitochondrial activity was significantly reduced. A hyperglycemia (175 mg . dl-1) at 3 h changed into a hypoglycemia (50 mg . dl-1) at 6 h. It is suggested that Ld plus Etx causes a rapid impairment of hepatic mitochondria which leads to a drastic disturbance of the hepatic energy metabolism including hypoglycemia and contributes to an enhanced lethality in Ld-sensitized endotoxicosis.

Protective Effects of Urinary Trypsin Inhibitor in Experimental Shock

The effects of human urinary trypsin inhibitor (UTI) were studied in experimental shock models. Administration of 50,000 U/kg, i.v., of UTI protected against mortality from shock induced by burn, endotoxin or trauma. Aprotinin at a dose of 50,000 U/kg improved only endotoxin shock and showed a moderate but not significant effect on burn and traumatic shock. Administration of 50,000 U/kg, i.v., of UTI protected against the aggravation in systemic hemodynamics in canine hemorrhagic shock. Furthermore, in rat traumatic shock, 50,000 U/kg, i.v., administration of UTI significantly reversed the increased serum beta-glucuronidase and trypsin activities and the decreased hepatic ATP level, and it moderately suppressed the increased serum uric acid level. Aprotinin failed to affect all these biochemical changes induced by drum trauma. These results suggest that the protective effect of UTI against experimental shock is possibly exerted through lowering the elevated enzyme activities in the serum during shock.

Fetal and neonatal responses to extended maternal canine starvation. II. Fetal and neonatal liver metabolism.

Summary: The effects of maternal canine starvation (MCS) for 5 days on hepatic intermediates in fetus and fasted neonates were studied at 0, 3, 6, 9, and 24 h of age. Maternal starvation reduced the birth weights of the pups by 23% (232 ± 6 versus 300 ± 10 g). In the MCS fetuses, hepatic glycogen concentration was significantly decreased (416 versus 526 μmole/g) whereas uridine diphosphate glucose concentration was significantly increased (0.196 versus 0.135 μmole/g), suggesting diminished glycogen synthetase activity. After birth, hepatic glucose levels were significantly decreased at 3 (2.90 versus 5.95 μmole/g) and 24 (3.09 versus 5.29) h in the MCS pups. Glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P) levels were low in MCS pups throughout the study, G6P being significantly decreased at 9 and 24 h, and F6P at 0, 6, 9, and 24 h in the MCS group. Fructose 1,6-diphosphate did not show any changes among groups. Of greater importance, hepatic ATP concentrations were significantly reduced in the MCS pups throughout the first day of life. Maternal fasting results in attenuated fetal hepatic glycogen synthesis and an altered transition from fetal to neonatal life. Diminished G6P and F6P levels suggest that hepatic glycolytic activity may be enhanced at the level of phosphofructokinase. In the presence of lactate carbon incorporation into glucose that approaches control rates of gluconeogenesis, the diminished G6P and F6P levels also suggest significant recycling of lactate carbon between glucose and lactate. Furthermore, despite the apparent predominance of glycolysis, diminished hepatic ATP levels suggest that MCS plus neonatal fasting produced a hepatic energy deficiency state. Hepatic substrate deficiency and altered energy production may result from the diversion of glycogen derived glucose to support systemic glucose production.

Regulation of glucose production from lactate in experimental sepsis.

Gluconeogenic and oxidative capabilities with lactate as a substrate were studied in perfused livers isolated from rats in late sepsis. Glucose release in the presence of 5 mM lactate was significantly depressed in livers from septic rats. When gluconeogenesis was stimulated by phenylephrine, livers from septic rats exhibited both a decreased sensitivity and lower maximal rate of glucose release when compared with livers from sham-operated rats. Oxygen consumption (VO2) by perfused livers from septic rats was also depressed under the above conditions. The addition of lysine in concentrations greater than 0.5 mM restored glucose production in livers from septic rats to a rate not different from sham-operated controls but did not restore VO2. However, inclusion of lysine (5 mM) in the perfusate was not able to restore sensitivity to stimulation by phenylephrine in livers from septic rats. Although hepatic ATP levels were depressed in sepsis, the decrease was not sufficient to explain the decreased rates of glucose production. We conclude from these results that primary cellular defects in gluconeogenic and oxidative capabilities occur during sepsis that are independent of inadequate perfusion.

Studies on the mechanism of beneficial effects of ATP-MgCl2 following hepatic ischemia.

Infusion of ATP-MgCl2 following hepatic ischemia significantly improves the survival of animals. To determine the subcellular effects of infused ATP-MgCl2 and whether such effects are mediated through vasodilatation, global hepatic ischemia in rats was produced for 90 min followed by reperfusion. The rats then received iv 0.5 ml of saline, dopamine, papaverine, or ATP-MgCl2. At various intervals following reflow, hepatic mitochondria were isolated. ADP-to-O ratio and respiratory control ratio (RCR) were significantly lower 1 h following reflow, and there was a further decrease in these parameters 3 h after reflow in mitochondria from saline-treated rats. Dopamine and papaverine treatment did not improve RCR, however, ATP-MgCl2 treatment resulted in a progressive and significantly higher ADP/O and RCR following reflow. Hepatic ATP levels in saline, dopamine, and papaverine-treated rats were found to be 50% lower 3 h following reflow, however, treatment with ATP-MgCl2 resulted in significantly higher ATP levels and energy charge. Hepatic blood flow was markedly depressed 1 h following reflow in the saline-treated rats but was significantly higher in the ATP-MgCl2 group. Three hours following reflow, hepatic blood flow decreased further in the saline-treated rats, whereas in the ATP-MgCl2-treated rats there was a progressive increase in flow. Dopamine treatment resulted in an initial restoration in flow, however, this effect was not sustained. Hepatic ultrastructure deteriorated progressively following reflow in the saline-treated rats, however, it was normal in the ATP-MgCl2-treated rats 1 h as well as 20 h following reflow. These results lead us to conclude that infused ATP-MgCl2 improves mitochondrial and cellular functions either directly or by way of long-term improvement in microcirculation but not through vasodilatation.

Hepatic and cerebral energy metabolism after neonatal canine alimentation.

Intrahepatic and intracerebral metabolic responses to neonatal fasting or enteric carbohydrate alimentation were investigated among newborn dogs. Pups were either fasted or given an intravenous glucose infusion (alimented) before an enteric feeding of physiologic quantities of either glucose or galactose. These pups were also compared to another group which was completely starved throughout the study period. Gastrointestinal carbohydrate feeding resulted in enhanced hepatic glycogen content among pups after a prior state of fasting. Though there were no differences of glycogen content between glucose or galactose feeding in this previously fasted group, combined intravenous glucose and enteric galactose administration produced the greatest effect on hepatic glycogen synthesis. Intrahepatic fructose 1, 6-diphosphate and phosphoenolpyruvate levels were increased among previously fasted pups fed enteric monosaccharides compared to completely starved control pups, whereas intrahepatic phosphoenolpyruvate and pyruvate levels were elevated after combined intravenous and enteric carbohydrate administration. Of greater interest was the observation that hepatic levels of ATP were significantly elevated among all groups given exogenous carbohydrates compared to the completely starved control group. In contrast to the augmented hepatic glycogen and ATP levels, there were no alterations of cerebral glycogen or ATP after alimentation. Nevertheless, cerebral pyruvate and/or phosphoenolpyruvate concentrations were elevated after enteric or combined intravenous and enteric alimentation compared to the totally starved control pups.

Effect of prostaglandin on cell membrane permeability and hepatic high-energy stores following hemorrhagic shock

Infusion of prostaglandin E 1 is known to exert a beneficial effect in hemorrhagic shock. It is also known that hemorrhagic shock lowers hepatic stores of high-energy phosphates and that restoration of hepatic ATP is associated with improved organ function and survival. The present study was undertaken to evaluate the effect of infusion of exogenous prostaglandin E 1 on (1) hepatic ATP levels and (2) restoration of hepatic ATP-dependent intracellular function. Rats were subjected to hemorrhagic shock, resuscitated, and then treated with either prostaglandin E 1 or a saline placebo. Ten minutes after the completion of treatment, hepatic ATP levels were significantly higher in prostaglandin-treated animals (1.37 ± 0.43 μmol/g) than in animals receiving the placebo (0.70 ± 0.11 μmol/g). Creatine phosphate levels were also higher in the prostaglandin-treated group (1.59 ± 0.16 μmol/g) than in the placebo-treated group (0.89 ± 0.14 μmol/g). Lactate production ratios, an index of ATP-dependent membrane function, were near the theoretical normal of 100% in unshocked, untreated animals (95 ± 10%). They were significantly reduced (57 ± 10%) in animals receiving only placebo, but were not significantly different from unshocked animals in those receiving prostaglandin E 1 following shock (91 ± 10%). It is concluded that prostaglandin infusion improves both hepatic high-energy phosphate levels and ATP-dependent intracellular function following hemorrhagic shock. This might be due to replenishing the purine base, selectively increasing hepatic blood flow, or both.

Effect of prolonged starvation on reticuloendothelial function and survival following trauma.

The effects of prolonged starvation on reticuloendothelial system (RE) function and on the survival of animals following trauma were studied. Rats were fasted for 51/2 days (water ad lib) after which a two-cm midline incision was made and the cecum ligated (CL). Food and water were allowed 36 h after CL and survival was measured over 5 days. The mortality rate in these animals was 60% (15/25) compared to 0% (0/15) in CL rats fasted for 24 h. Starvation alone for 7 days did not produce any deaths but after 11 days of starvation mortality was 100%. Another group of animals were fasted for 51/2 days and were used to study RE function 10 h following CL. There was no significant difference in the intravascular clearance rates in injected lipid emulsion in various groups of animals, indicating that total phagocytic function was not changed by prolonged starvation plus CL (SCL). However, emulsion retention in the spleen, expressed as per cent injected dose per gm tissue, decreased by 53% and the lung retention increased by 988% following SLC. Serum GOT levels were not affected by prolonged starvation alone; however, SCL resulted in its elevation (37 vs. 82 IU/ml). Hepatic ATP levels (micromoles/g) decreased from 2.47 to 1.95 following 51/2 days starvation and following SCL, it decreased to 1.75. These results indicate that the increased metabolic demand following trauma (i.e., CL), coupled with prolonged starvation, altered RE function with splenic lipid emulsion uptake decreasing and pulmonary uptake increasing. The relationship of these findings to immune function remains to be determined. Although the precise cause of increased mortality is not known, altered metabolic and RE function may play a role.

Maintenance of rat liver viability enhanced by cold flushing with oxygenated perfluorochemicals.

The possible benefit of oxygenation during initial cold flushing was investigated as means of improving the quality of live preservation in rats. In five group of animals (total 61 experiments), the lives were flushed with different perfusates. Non-oxygenated groups included controls, Collins' solution alone and Collins' solution containing perfluorotributylamine (FC-43). In the oxygenated groups, Collins' solution alone and collins' solution containing FC-43 were oxygenated by bubbling. The hepatic ATP level and histopathological changes were used to assess the quality of liver preservation. Oxygenation during the initial cooling process proved to be effective in maintaining energy metabolism and preventing the characteristic microscopic changes of ischemic damage. Oxygenated Collins' solution containing FC-43 showed a much longer lasting effect compared with oxygenated Collins' solution alone. Without FC-43. Under light microscopy, in integrity of the liver appeared to be well preserved up to eight hours with the former solution. It is concluded that enhanced oxygenation with FC-43 in the initial cold flushing period can improve the quality of liver preservation.

1164 EFFECT OF EXTENDED MATERNAL STARVATION ON THE INTRAHEPATIC REGULATION OF METABOLISM IN NEWBORN DOGS

Hepatic metabolic intermediates from fasted newborn pups of 6 control and eight 5-day starved pregnant mothers (MCS) were studied between 0 and 24 hrs of age. In the MCS fetus, glycogen concentrations were significantly reduced (416vs526 μ mol/g)+ and uridinediphosphate glucose levels increased (0.196vs0.135) suggesting diminished fetal glycogen synthesis. After birth glycogen levels diminished at the same rate in the 2 groups being 197 and 304 at 24 hrs. Hepatic glucose concentrations were reduced in the MCS pups at 3 hrs (2.90vs5.97) reaching control levels at 6 and 9 hrs, again declining at 24 hrs (3.09vs5.29). Glucose-6-phosphate and fructose-6-phosphate concentrations after MCS were low in the fetus and throughout the 24 hrs. Tricarboxylic acid cycle (TCA) intermediates tended to be low after 6 hrs in the MCS group; α-ketoglutarate levels being significantly reduced at 6 and 9 hrs, malate at 9 and 24 hrs, and citrate at 24 hrs. After birth, MCS resulted in significant lowering of hepatic ATP levels while energy charge was low only at 6 and 9 hrs. In addition the cytoplasmic NAD/NADH ratio was significantly more oxidized at 3 hrs in the MCS pups. Intrahepatic ammonia concentrations were significantly elevated at 0,6,9 and 24 hrs. CONCLUSION: Extended MCS results in 1)reduced fetal glycogen synthesis or augmented fetal glycogenolysis and 2)diminished hepatic energy production after birth in spite of enhanced net hepatic glycolytic flux as a result of phosphofructokinase activation by low levels of ATP, citrate and NADH. *Deceased +Mean

Effects of a single therapeutic dose of glycerol on cerebral metabolism in the brains of young mice: possible increase in brain glucose transport and glucose utilization.

Abstract: This is a study of the effects of a single “therapeutic” dose of glycerol [2 g(22 mmol)/kg i.p.] on brain carbohydrate and energy metabolism in normal nursing weanling mice. Findings were correlated with brain water and electrolyte content and with metabolite changes in plasma, red blood cells, and liver.Plasma glycerol levels peaked at 21 mM 7.5 min after injection and returned to the control value, 0.16 mM, by 2 h. Plasma Na+ concentration decreased and plasma protein increased for as long as 2 h after injection. Although red blood cells were freely permeable to glycerol, there was no evidence for glycerol metabolism in these cells. Glycerol levels in liver paralleled those in plasma. Glycerol injection increased liver glucose concentration 23% and doubled hepatic glycerol‐1‐phosphate levels. Liver ATP levels were reduced 24% after glycerol injection.Brain water concentration was significantly reduced from 7.5 min to 30 min after glycerol injection; brain Na+ and K+ levels were unchanged. There was no evidence for glycerol entry into brain (the amount detected in brain tissue could be explained by the glycerol content in the blood of the brain). While plasma glucose increased 33%, brain glucose increased 87%. Concomitantly there were statistically significant increases in fructose‐1,6‐diphosphate, lactate, α‐ketoglutarate, and malate levels.The disproportionately high brain glucose value suggests increased transport of glucose from the blood to the brain. Increases in fructose‐1,6‐diphosphate, lactate, α‐ketoglutarate, and malate are compatible with an increased metabolic flux in the glycolytic pathway and Krebs citric acid cycle. As has been previously shown for urea and/or mannitol, these changes may result from the effects of the hyperosmolar glycerol solution on the blood‐brain barrier and on cerebral glucose utilization.The sustained lowering of plasma Na+ concentration after a single “therapeutic” glycerol injection suggests a need for monitoring plasma Na+ levels in the clinical situation. Possible lowering of hepatic ATP levels by the use of glycerol in humans is another concern.

Effect of adenosine tri phosphate-glucose administration following sepsis

Sepsis in rats was produced in cecal ligation and puncture. Sixteen hours later, the peritoneal cavity was reopened, the gangrenous cecum removed, and the cavity irrigated with warm saline. Animals which were normotensive then received iv either: (a) saline (controls), (b) glucose (50%) plus saline, or (c) ATP-MgCl 2 (12.5 or 100 μmole ATP and 12.5 or 50 μmole MgCl 2) with or without hypertonic glucose plus saline. Following the infusion of one of the above, survival was measured over a period of 5 days. The results indicate that there was no statistical difference in the survival rate of rats given saline, glucose, ATP-MgCl 2 alone, or lower concentrations of ATP-MgCl 2 with glucose. However, infusion of ATP-MgCl 2 (100 μmole ATP + 50 μmole MgCl 2) plus glucose (ATP-MgCl 2-G), resulted in a significant increase in the survival of animals. Thus, the septic hypoglycemic rats required glucose together with higher ATP-MgCl 2 concentrations for treatment to be effective. Hepatic and renal ATP levels decreased during sepsis; however, infusion of higher concentrations of ATP-MgCl 2 alone or together with glucose resulted in the restoration of cellular ATP levels within 3 hr. Infusion of glucose alone did not restore cellular ATP levels. Reticuloendothelial system (RES) function was depressed during sepsis; however, infusion of ATP-MgCl 2-G resulted in the restoration of RES function. The precise mechanism of the salutary effects of ATP-MgCl 2-G on survival is not clear. The results presented here indicate that extirpation of the lesion producing the septic process and metabolic support proved helpful without antibiotic treatment.

On the mechanism of ethanol-induced fatty liver and its reversibility by adenosine

The administration of adenosine partially prevented and reverted the ethanol-induced fatty liver. The hepatic α-glycerophosphate concentration and the α-glycerophosphate/dihydroxyacetone phosphate ratio were significantly increased after ethanol administration. The nucleoside decreased with ratio and enhanced the oxidation of ethanol. A strong correlation between the cytoplasmic redox state and the amount of triacylglycerols in the liver was found (8 h after treatments) stressing the paramount importance of the redox state in the pathogenesis of ethanol-induced fatty liver. As previously reported, the nucleoside expanded the adenine nucleotide pool size and the hepatic ATP level. Ethanol potentiated these effects. It is suggested that adenosine ameliorated the ethanol-induced fatty liver through an increased utilization of reducing equivalents by the mitochondria. An interdependence of these effects is proposed and discussed.

Depression by ethionine of phosphorylating oxidation in hepatic mitochondria.

Induction of hepatic steatosis and suppression of hepatic ATP levels, protein synthesis and gluconeogenesis subsequent to administration of ethionine may be consequences of interference by this compound with mitochondrial phosphorylation of ADP. The mitochondrial dysfunction is not a direct action of ethionine on the organelle.

Effects of rubratoxin B on hepatic ATP and cyclic AMP levels in mice

Rubratoxin B produced in mice a significant decrease in hepatic levels of cyclic AMP (cAMP), 1 h after i.p. injection. The toxin also significantly decreased levels of hepatic ATP, but this effect was not seen until 18 h post treatment. Therefore, the reported rubratoxin B-induced decrease in liver glycogen is not mediated through effects on cAMP or ATP. Rather, these actions of the toxin appear to be unrelated aspects of a hepatotoxicity.

Effect of chronic ethanol consumption on liver metabolites in Sinclair (S-1) miniature swine

1. 1. The nature and extent of changes in levels of liver metabolites, as a result of chronic ethanol consumption, were investigated using miniature swine as experimental subjects. 2. 2. Mean ethanol consumption was in excess of 6.0 g ethanol/kg body weight per day. 3. 3. Mean hepatic tissue concentrations of triglycerides, NADH and β-hydroxybutyrate, as well as the β-hydroxybutyrate/acetoacetate ratio, were greater for pigs fed ethanol than for controls. 4. 4. Mean hepatic tissue levels of glycogen and ATP, as well as the NAD +/NADH ratio and energy charge, were less for pigs fed ethanol than for controls.

Effect of dietary fructose on in vitro and in vivo fatty acid synthesis in the rat

Diets containing either glucose or fructose as the only source of carbohydrate were fed to rats. [U- 14C] Glucose and [U- 14C] fructose incorporation into fatty acids by liver slices from these animals indicated that the results obtained were markedly affected by substrate concentration. At a level of 10 mM fructose incorporation into hepatic fatty acids was greater than that observed with glucose; however, the reverse was true when the substrate concentration was increased to 100 mM. High levels of fructose in the incubation medium markedly depressed ATP levels in liver slices and also inhibited [ 14C]-acetate incorporation into fatty acids. Rats fed fructose had higher hepatic ATP levels than did rats fed glucose. In vivo estimates of fatty acid synthesis were obtained using [ 14C] acetate as well as 3H 2. These determinations indicated that while the total capacity of the animal to synthesize fatty acids was unchanged, the relative importance of the liver was increased and that of the extra-hepatic tissues decreased when fructose, rather than glucose, was fed to rats.

The Effect of Cycloheximide on the Interaction between Mitochondrial Respiration and Gluconeogenesis in Guinea Pig and Rat Liver

Abstract Cycloheximide (3 to 5mm) caused a decrease in the rate of gluconeogenesis from pyruvate, lactate, or glycerol in the perfused rat and guinea pig liver. In these experiments, oxygen consumption was reduced by 30% with pyruvate but was unaltered with lactate or glycerol as substrates. The inhibition of gluconeogenesis caused by cycloheximide was rapid in onset (100% of maximal inhibition in 1 to 2 min) and immediately reversible upon cessation of cycloheximide infusion. Perfused livers were freeze-clamped in situ before and during cycloheximide infusion and the mitochondrial NAD:NADH ratio was calculated by a measurement of intermediates of the β-hydroxybutyrate dehydrogenase couplet. There was a marked shift toward reduction of the intramitochondrial pool of nicotinamide coenzymes after cycloheximide infusion. Under these conditions, the hepatic levels of ATP, ADP, and AMP were not significantly altered by cycloheximide in livers of rats perfused with lactate. With pyruvate as substrate, the ratio of ATP:ADP was decreased although no change in AMP levels was observed. Our findings indicate that the metabolic effects of cycloheximide are rapidly reversed, with the inhibitory effect on gluconeogenesis not evident after 10 min of recycling of the perfusate through the liver. Previous studies with cycloheximide have shown this compound to block mitochondrial energy transfer at Site I of the respiratory chain. It is suggested that cycloheximide decreases the rate of hepatic gluconeogenesis by an inhibition of mitochondrial energy transfer at Site I.