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PubMed2002

Tartrate dehydrogenase catalyzes the stepwise oxidative decarboxylation of D-malate with both NAD and thio-NAD.

Tartrate dehydrogenase catalyzes the divalent metal ion- and NAD-dependent oxidative decarboxylation of D-malate to yield CO(2), pyruvate, and NADH. The enzyme also catalyzes the metal ion-dependent oxidation of (+)-tartrate to yield oxaloglycolate and NADH. pH-rate profiles and isotope effects were measured to probe the mechanism of this unique enzyme. Data suggest a general base mechanism with likely general acid catalysis in the oxidative decarboxylation of D-malate. Of interest, the mechanism of oxidative decarboxylation of D-malate is stepwise with NAD(+) or the more oxidizing thio-NAD(+). The mechanism does not become concerted with the latter as observed for the malic enzyme, which catalyzes the oxidative decarboxylation of L-malate [Karsten, W. E., and Cook, P. F. (1994) Biochemistry 33, 2096-2103]. It appears the change in mechanism observed with malic enzyme is specific to its transition state structure and not a generalized trait of metal ion- and NAD(P)-dependent beta-hydroxy acid oxidative decarboxylases. The V/K(malate) pH-rate profile decreases at low and high pH and exhibits pK(a) values of about 6.3 and 8.3, while that for V/K(tartrate) (measured from pH 7.5 to pH 9) exhibits a pK(a) of 8.6 on the basic side. A single pK(a) of 6.3 is observed on the acid side of the V(max) pH profile, but the pK(a) seen on the basic side of the V/K pH profiles is not observed in the V(max) pH profiles. Data suggest the requirement for a general base that accepts a proton from the 2-hydroxyl group of either substrate to facilitate hydride transfer. A second enzymatic group is also required protonated for optimum binding of substrates and may also function as a general acid to donate a proton to the enolpyruvate intermediate to form pyruvate. The (13)C isotope effect, measured on the decarboxylation of D-malate using NAD(+) as the dinucleotide substrate, decreases from a value of 1.0096 +/- 0.0006 with D-malate to 1.00787 +/- 0.00006 with D-malate-2-d, suggesting a stepwise mechanism for the oxidative decarboxylation of D-malate. Using thio-NAD(+) as the dinucleotide substrate the (13)C isotope effects are 1.0034 +/- 0.0007 and 1.0027 +/- 0.0002 with D-malate and D-malate-2-d, respectively.

Alcohol Oxidoreductases↗
PubMed1999

Peroxisome proliferators as adjuvants for the reverse-electron-transport therapy of obesity: an explanation for the large increase in metabolic rate of MEDICA 16-treated rats.

The efficacy of reverse-electron-transport therapy of obesity should be promoted by agents which up-regulate hepatocyte enzymes that are potentially rate-limiting for mitochondrial fatty acid oxidation and electron shuttles. Peroxisome proliferator drugs, including the fibrates used to treat hyperlipidemia, may be useful in this regard, as they induce malic enzyme, the mitochondrial glycerol-3-phosphate dehydrogenase, and carnitine palmitoyl transferase I in rodent hepatocytes. An agent of this class, MEDICA 16, has the additional property of potently inhibiting both citrate lyase and acetyl-CoA carboxylase. As a result, methyl-substituted diacarboxylic acids (MEDICA) 16 can be expected to disinhibit hepatic fatty acid oxidation while up-regulating electron shuttle mechanisms, and thus should stimulate reverse electron transport. This may explain the remarkable 40% increase in basal metabolic rate observed in normal rats ingesting MEDICA 16--an effect not associated with any compensatory increase in food intake. Relative to controls, the MEDICA 16-treated rats achieved a 50% reduction in body fat and a modest increase in lean mass, such that weight and growth were not changed. In other rodent strains, MEDICA 16 has prevented obesity diabetes and atherogenesis. However, whether MEDICA 16 and other peroxisome proliferator drugs will have clinical utility in reverse-electron-transport therapy may hinge on their ability to induce key enzymes in human hepatocytes; cell culture studies to evaluate this are required.

Acetyl-CoA Carboxylase↗
PubMed1984

Determination of dissociation constants for enzyme-reactant complexes for NAD-malic enzyme by modulation of the thiol inactivation rate.

Incubation of NAD-malic enzyme from Ascaris suum with the sulfhydryl reagents N-ethylmaleimide (NEM), 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), or 4,4'-dithiodipyridine (4-PDS) results in rapid and complete loss of malate oxidative decarboxylase and pyruvate reductive carboxylase activities. With DTNB, this loss of activity occurs concomitantly with the modification of about 1 thiol group per subunit. The majority of the activity is lost when 0.5 thiol per subunit is modified, indicative of possible half-site reactivity with DTNB. Complete restoration of activity follows addition of dithiothreitol to enzyme inactivated by DTNB and 4-PDS but not with NEM. With the DTNB-inactivated enzyme, replacement of the thionitrobenzoate moiety with cyanide restores activity. The presence of a divalent metal ion (Mg2+ or Mn2+) results in enhancement of the inactivation rate with all sulfhydryl reagents. However, malate alone or competitors of malate provide protection which is more effective in the presence of Mg2+, while NAD provides only about 25% protection. Thus, the Ascaris suum NAD-malic enzyme has a thiol group probably located in or near the malate binding site, which is not essential for enzyme activity. The changes in the rate of inactivation in the presence of reactants were used to determine the dissociation constants for enzyme-reactant complexes. These data suggest that all three possible binary and all three possible ternary complexes form. The binding of malate to free enzyme exhibits negative cooperativity, which is eliminated by the presence of either NAD or Mg2+.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Influence of dietary conjugated linoleic acid on growth, meat quality, lipogenesis, plasma leptin and physiological variables of lipid metabolism in rabbits.

We investigated the effects of conjugated linoleic acid (CLA) supplementation on growth, feed efficiency, carcass characteristics, meat quality, lipogenesis, and lipid metabolism in rabbits. One hundred forty-four New Zealand White rabbits, half males, half females, age 55 d, mean 1.8 kg BW, were randomly assigned to three weight- and sex-balanced feeding groups in which conventional pelleted diets were supplemented with 0, 0.25, or 0.5% of a CLA preparation. The CLA preparation contained 65% CLA isomers. Twelve rabbits (six males and six females from each group) were slaughtered at each of three slaughtering trials (2.5, 2.8, and 3.1 kg BW, or 76, 90, and 104 d of age). Conjugated linoleic acid supplementation did not influence growth performance (P > or = 0.05) or carcass characteristics but reduced perirenal fat at heavier slaughtering weights (P = 0.09 at 2.8 kg BW; P < 0.01 at 3.1 kg BW). Conjugated linoleic acid reduced acetyl-CoA-carboxylase (CBX) activity in liver (P < 0.05) and adipose tissues (P < 0.01) but did not influence malic enzyme (ME) or glucose-6-phosphate dehydrogenase activity. Significant differences were found between sex in interscapular fat (P < 0.05) for CBX, in perirenal (P < 0.01) and interscapular (P < 0.05) fat for ME, and a tendency (P = 0.070) in liver for glucose-6-phosphate dehydrogenase. The oxidative stability of longissimus lumborum muscle was increased at the higher level of supplementation (P < 0.05). Conjugated linoleic acid reduced (P < 0.05) triglycerides and total cholesterol in plasma with a trend to increased serum leptin (P = 0.06). Plasma triglycerides were higher in males than females (P < 0.01) and plasma leptin tended to be higher in females (2.57 vs. 2.13 ng/ml, P = 0.06). It is concluded that dietary CLA reduced carcass fat in rabbits slaughtered at 2.8 kg or above and altered lipid metabolism to produce lower concentrations of serum triglycerides and total cholesterol and higher concentrations of leptin.

Animal Feed↗
PubMed1999

Crystal structure of human mitochondrial NAD(P)(+)-dependent malic enzyme: a new class of oxidative decarboxylases.

Background: Malic enzymes catalyze the oxidative decarboxylation of malate to pyruvate and CO(2) with the concomitant reduction of NAD(P)(+) to NAD(P)H. They are widely distributed in nature and have important biological functions. Human mitochondrial NAD(P)(+)-dependent malic enzyme (mNAD-ME) may have a crucial role in the metabolism of glutamine for energy production in rapidly dividing cells and tumors. Moreover, this isoform is unique among malic enzymes in that it is a cooperative enzyme, and its activity is controlled allosterically. Results: The crystal structure of human mNAD-ME has been determined at 2.5 Å resolution by the selenomethionyl multiwavelength anomalous diffraction method and refined to 2.1 Å resolution. The structure of the monomer can be divided into four domains; the active site of the enzyme is located in a deep cleft at the interface between three of the domains. Three acidic residues (Glu255, Asp256 and Asp279) were identified as ligands for the divalent cation that is required for catalysis by malic enzymes. Conclusions: The structure reveals that malic enzymes belong to a new class of oxidative decarboxylases. The tetramer of the enzyme appears to be a dimer of dimers. The active site of each monomer is located far from the tetramer interface. The structure also shows the binding of a second NAD(+) molecule in a pocket 35 Å away from the active site. The natural ligand for this second binding site may be ATP, an allosteric inhibitor of the enzyme.

Journal Article↗
PubMed1988

Lipogenic enzyme induction and incorporation of exogenous fatty acid into liver and liver nuclei.

The incorporation of exogenous fatty acid into lipids of liver and liver nuclei of rats fed diets with or without fat was compared. When [3H]palmitic acid was injected into rats, more radioactivity was incorporated into triacylglycerols and phospholipids of liver and liver nuclei from rats fed the fat-free diet than from those fed the fat diet. The results were supported further by an autoradiographic study. On the other hand, the enzyme induction and quantity of malic enzyme mRNA were decreased by fat feeding. Other lipogenic enzymes were also coordinately decreased. Thus, it may be possible that exogenous fatty acid is involved in nuclear regulation in addition to cytosolic regulation of lipogenic enzyme induction.

Animals↗
PubMed1998

Effect of inclusion of cashew globulin (Anacardium occidentale) to a casein diet on lipid parameters in rats.

The effect of inclusion of cashew globulin to a casein diet on lipid metabolism was studied in rats fed diets with two levels of cashew globulin meal. Inclusion of cashew globulin to a casein diet produced lower levels of total cholesterol, triacylglycerol and phospholipids in the serum and tissues and lower levels of serum lipoprotein cholesterol. There was decreased cholesterogenesis in the liver as evidenced by decreased activity of HMG CoA reductase and decreased release of lipoproteins into circulation. Rats fed cashew globulin along with casein also showed higher activity of LPL in the heart and adipose tissue and higher activity of LCAT. Increased hepatic diversion of cholesterol to bile acid synthesis and increased excretion of bile acids and sterols were also observed in these groups. Activity of glucose-6-phosphate dehydrogenase and malic enzyme was decreased in rats fed cashew globulin along with casein. This study demonstrates that cashew globulins included in the diet of rats are able to alter lipid metabolism which results in lower levels of lipid parameters in the serum and tissues.

Adipose Tissue↗
PubMed1985

Effect on the interaction of dietary carbohydrate and fat on the responses of rats to starvation-refeeding.

The interacting effects of sucrose or starch with corn or coconut oil on the lipogenic responses of rats to starvation-refeeding was studied. Rats were either ad libitum-fed or starved for 48 h and refed for 48 h. Four different diets were used: 65% starch-5% corn oil, 65% starch-5% coconut oil, 65% sucrose-5% corn oil, 65% sucrose-5% coconut oil. Lipogenesis was assessed in two ways: glucose-6-phosphate dehydrogenase (G6PD) activity, malic enzyme (ME) activity and percent liver lipid (expt 1) and tritium (3HOH) incorporation into fatty acids (expt 2). Starved-refed rats had more liver lipid, greater enzyme activity and greater 3H incorporation into fatty acids than ad libitum-fed rats. Sucrose-fed rats had more lipogenic activity than starch-fed rats. Rats fed coconut oil were more lipogenic than rats fed corn oil. There were highly significant correlation coefficients between the enzyme activities (G6PD and ME) and the percent liver lipid and between the enzyme activities and 3H incorporation into fatty acid. Analysis of variance of these data revealed significant dietary effects on these lipogenic responses to starvation-refeeding. We conclude that both dietary carbohydrate and lipid play a significant role in the determination of the magnitude of the lipogenic response to starvation-refeeding.

Animals↗
PubMed1973

Phosphoenolpyruvate carboxykinase in plants exhibiting crassulacean Acid metabolism.

Phosphoenolpyruvate carboxykinase has been found in significant activities in a number of plants exhibiting Crassulacean acid metabolism. Thirty-five species were surveyed for phosphoenolpyruvate carboxykinase, phosphoenolpyruvate carboxylase, ribulose diphosphate carboxylase, malic enzyme, and malate dehydrogenase (NAD). Plants which showed high activities of malic enzyme contained no detectable phosphoenolpyruvate carboxykinase, while plants with high activities of the latter enzyme contained little malic enzyme. It is proposed that phosphoenolpyruvate carboxykinase acts as a decarboxylase during the light period, furnishing CO(2) for the pentose cycle and phosphoenolpyruvate for gluconeogenesis.Some properties of phosphoenolpyruvate carboxykinase in crude extracts of pineapple leaves were investigated. The enzyme required Mn(2+), Mg(2+), and ATP for maximum activity. About 60% of the activity could be pelleted, along with chloroplasts and mitochondria, in extracts from leaves kept in the dark overnight.

Journal Article↗
PubMed2003

Induced expression of the gene for NADP-malic enzyme in leaves of Aloe vera L. under salt stress.

A cDNA fragment for NADP-malic enzyme, catalyzing the reversible oxidative decarboxylation of L-malate to produce CO(2), pyruvate and NADPH, was isolated from the leaves of a 2-month-old Aloe vera L., The level of expression of NADP-ME mRNA and accumulation of NADP-ME (AvME) protein under salt stress conditions were compared between a tolerant aloe, Aloe vera L. and a sensitive aloe, Aloe saponarea Haw. The results suggested that both the expression of the gene and the accumulation of the protein were induced in the two kinds of aloe, and the strength was related to the degree of salt tolerance. Northern blot analysis revealed that the gene for NADP-malic enzyme in Aloe vera L.( AvME) was induced by high salt, dehydration, and exogenous abscisic acid (ABA), but not by cold treatment. To further confirm whether the synthesis of AvME protein was induced with hours of treatment, Western blot analysis of the samples was conducted. The results indicated that the induction of AvME protein expression was obvious after 48 h at high salt and the level was increased with the hours of treatment.

Abscisic Acid↗
PubMed2001

Increase of lipogenic enzyme mRNA levels in rat white adipose tissue after multiple cycles of starvation-refeeding.

Recently, we have found that despite the significant reduction of body weight after multiple starvation-refeeding cycles, white adipose tissue (WAT) exhibits surprisingly high rates of lipogenesis and lipogenic enzyme activities. The purpose of this study was to determine the response of WAT lipogenic enzyme mRNAs of rats subjected to multiple cycles of 3 days fasting and 3 days of refeeding. Despite the body weight reduction, significant increase of lipogenic enzymes (ie, fatty acid synthase [FAS], acetyl-coenzyme A [CoA] carboxylase [ACC], adenosine triphosphate (ATP)-citrate lyase [ACL], NADP-linked malic enzyme [ME], and glucose 6-phosphate dehydrogenase [G6PDH]) mRNAs in WAT was found after multiple cycles of starvation-refeeding of rats on standard laboratory diet. These findings, together with the results published recently, indicate that multiple cycles of starvation-refeeding cause the increased lipogenesis in WAT by upregulation of the lipogenic enzymes gene expression.

Adipose Tissue↗
PubMed2004

Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response.

Severe sepsis results in the decreased uptake and oxidation of fatty acids in the heart and cardiac failure. Some of the key proteins required for fatty acid uptake and oxidation in the heart have been shown to be downregulated after endotoxin (LPS) administration. The nuclear hormone receptors, peroxisome proliferator-activated receptor (PPAR) and thyroid receptor (TR), which heterodimerize with the retinoid X receptor (RXR), are important regulators of fatty acid metabolism and decrease in the liver after LPS administration. In the present study, we demonstrate that LPS treatment produces a rapid and marked decrease in the mRNA levels of all three RXR isoforms, PPARalpha and PPARdelta, and TRalpha and TRbeta in the heart. Moreover, LPS administration also decreased the expression of the coactivators CREB-binding protein (CBP)/p300, steroid receptor coactivator (SRC)-1, SRC-3, TR-associated protein (TRAP)220, and PPARgamma coactivator (PGC)-1, all of which are required for the transcriptional activity of RXR-PPAR and RXR-TR. In addition, the mRNA levels of the target genes malic enzyme, Spot 14, sarcoplasmic reticulum Ca2+-ATPase, or SERCA2, the VLDL receptor, fatty acyl-CoA synthetase, fatty acid transporter/CD36, carnitine palmitoyltransferase Ibeta, and lipoprotein lipase decrease in the heart after LPS treatment. The decrease in expression of RXRalpha, -beta, and -gamma, PPARalpha and -delta, and TRalpha and -beta, and of the coactivators CBP/p300, SRC-1, SRC-3, TRAP220, and PGC-1 and the genes they regulate, induced by LPS in the heart, could account for the decreased expression of key proteins required for fatty acid oxidation and thereby play an important role in cardiac contractility. These alterations could contribute to the myocardial dysfunction that occurs during sepsis.

Acute-Phase Reaction↗
PubMed1996

Characterization of a polypyrimidine/polypurine tract in the promoter of the gene for chicken malic enzyme.

Starvation inhibits and refeeding stimulates transcription of the malic enzyme gene in chick liver. DNA between -320 and +72 base pairs (bp) is DNase I-hypersensitive in hepatic nuclei from fed but not starved chicks (Ma, X. J., and Goodridge, A. G. (1992) Nucleic Acids Res. 20, 4997-5002). A polypyrimidine/polypurine (PPY/PPU) tract lies within the DNase I-hypersensitive region. In hepatocytes transiently transfected with plasmids containing triiodothyronine response elements and a minimal promoter from the malic enzyme gene linked to the chloramphenicol acetyltransferase gene, deletion of the PPY/PPU tract inhibited chloramphenicol acetyltransferase activity by about 90% with or without triiodothyronine. Fine mapping of S1 nuclease-sensitive sites suggests that the PPY/PPU tract can assume different isoforms of non-B-DNA, some of which may be triplex structures. The PPY/PPU tract contains specific binding sites for single- and double-stranded DNA binding proteins and, with 8 bp 3' of the tract, can function as a promoter. A (CT)7 repeat binds single-stranded DNA-binding protein and is essential for promoter activity. Two C-rich elements bind single-stranded DNA-binding proteins and may mediate inhibition of promoter function. The single- and double-stranded DNA-binding proteins that interact with the PPY/PPU tract may regulate transcription of the malic enzyme gene.

Animals↗
PubMed2004

Metabolism of [U-(13)C]leucine in cultured astroglial cells.

Leucine is rapidly metabolized in astroglial primary cultures. Therefore, it is considered as valuable fuel in brain energy metabolism. Only few of the leucine metabolites generated and released by astroglial cells have been identified. Therefore, a more detailed study was performed analyzing by NMR techniques the 13C-labeled metabolites, which were released by astroglial primary cultures during the degradation of [U-(13)C]leucine. Confirming a former radioactive study this analysis revealed 13C-labeled 2-oxoisocaproate and ketone bodies. Additionally, 13C-labeled alanine, citrate, glutamine, lactate and succinate were identified. Their detailed isotopomer analysis proves that 13C-labeled acetyl-CoA enters the tricarboxylic acid cycle, that intermediates with a characteristic 13C-labeling pattern can be withdrawn at several positions of the cycle, and that in the case of lactate and alanine there appears to be a participation of an active phosphoenolpyruvate carboxykinase and/or malic enzyme pathway. Thus, astroglial cells generate and release into the extracellular fluid not only the leucine catabolites 2-oxoisocaproate and ketone bodies, but also several tricarboxylic acid cycle dependent metabolites.

Animals↗
PubMed1978

Effect of Di-(2-ethylhexyl) phthalate (DEHP) on chemical constituents and enzymatic activity of rat liver.

Effect of Di(2-ethylhexyl) phthalate (DEHP), was investigated on chemical constituents and activity of certain enzymes of rat liver. A significant increase in liver weight; total and relative to body weight; decrease in total, free and esterified cholesterol; and no change in dry weight, moisture; RNA, DNA, total lipids, phospholipids, pyruvic acid and lactic acid contents was observed in liver of DEHP-treated rats as compared to controls. Activity of 3 mitochondrial enzymes, malic dehydrogenase, cytochrome-c-oxidase and diaphorase were significantly decreased while that of NADH-cytochrome c reductase, RNAase and DNAase remained unaltered upon treatment. The results suggest that DEHP exerts its hepatotoxic effects by interfering with bioenergetics of the cell.

Animals↗
PubMed1994

Cetaben is an exceptional type of peroxisome proliferator.

1. Cetaben in contrast to fibrates affect differently peroxisomal constituents. 2. Changes in large scale of liver non-peroxisomal parameters were compared after 10 days administration of equal doses (200 mg/kg/day) of cetaben and clofibric acid to male Wistar rats. 3. Clofibric acid treatment increased markedly the activities of FAD-glycerol-3-P dehydrogenase, beta-hydroxyacyl-CoA dehydrogenase, cytochrome-c oxidase, malic enzyme, NAD-glycerol-3-P dehydrogenase, ethoxycoumarin deethylase, p-nitroanisole demethylase and amounts of cytochrome P-450 and b5. 4. However no analogical changes were observed after cetaben treatment in the livers of experimental animals. 5. Both drugs increased the activities of alanine-glyoxylate aminotransferase-1 and acetylcarnitine transferase--enzymes with proven mitochondrial and peroxisomal location. 6. Cetaben contrary to clofibric acid does not increase solubilization of peroxisomal enzymes. 7. Enhanced acetylcarnitine transferase and alanine-glyoxylate aminotransferase-1 activities were distributed in mitochondria as well as in peroxisomes after clofibric acid treatment, however, only peroxisomes were enriched after cetaben administration. 8. The results obtained suggest that cetaben represents an exceptional type of peroxisome proliferator, specifically affecting peroxisomes, without having a negative influence on the processes of peroxisome biogenesis.

4-Aminobenzoic Acid↗
PubMed2003

Involvement of single residue tryptophan 548 in the quaternary structural stability of pigeon cytosolic malic enzyme.

Pigeon cytosolic malic enzyme has a double dimer quaternary structure with three tryptophanyl residues in each monomer distributed in different structural domains. The enzyme showed a three-state unfolding phenomenon upon increasing the urea concentration (Chang, H. C., Chou, W. Y., and Chang, G. G. (2002) J. Biol. Chem. 277, 4663-4671). At urea concentration of 4-4.5 m, where the intermediate form was detected, the enzyme existed as partially unfolded dimers, which were easily polymerized. Mn2+ provided full protection against the polymerization. To further characterize this phenomenon, three mutants of the enzyme (W129, W321, and W548), each with only one tryptophanyl residue left, were constructed. All these mutants were successfully overexpressed in Escherichia coli cells and purified to homogeneity. Changes in the circular dichroism spectra of all mutants revealed a three-state urea-unfolding process in the absence of Mn2+. In the presence of 4 mm Mn2+, W548 and wild type (WT) enzymes shifted to monophasic, while W129 and W321 were still biphasic. Similar results were obtained from the fluorescence spectral changes, except for W321, which showed monophasic denaturation curve with or without Mn2+. Analytical ultracentrifugation analysis indicated that the mutant enzymes were polymerized at 4.5 m urea, and Mn2+ provided protective effect on W548 and WT enzymes only. Other mutants with mutated Trp-548 polymerized at 4.5 m urea in the absence or presence of 4 mm Mn2+. The above results indicate that a single residue, Trp-548, in the subunit interface region, is responsible for the integrity of the quaternary structure of the pigeon cytosolic malic enzyme.

Amino Acid Substitution↗
PubMed1989

Lipogenesis and cholesterogenesis de novo in liver and adipose tissue. Alterations of lipid metabolism by the effect of short- and long-term thioacetamide administration to rats.

Enzyme activities related to fatty acid synthesis were determined in liver extracts of rats treated with thioacetamide (TAM) for 8 weeks. Lipogenesis and cholesterogenesis in vivo were evaluated both in liver and in epididymal adipose tissue. The enzymatic activities of ATP-citrate lyase, acetyl CoA carboxylase, fatty acid synthetase, glycerol kinase and NAD-kinase decrease progressively when TAM was chronically administered. However, in the same experimental conditions malic enzyme and other NADP-enzymes were noticeably increased. This increase can be related to an excess of NADPH production necessary for detoxification rather than for lipogenesis. The rate of in vivo incorporation of 3H2O into non-saponifiable fraction in liver showed an increase in the acute phase (1-3 days) of TAM-treatment. In the chronic phase of TAM intoxication this rate returned to values close to normality. The rate of in vivo incorporation of 3H2O to fatty acid fraction increased in the liver during the acute phase of TAM-treatment and showed a sharp decrease during the subacute and chronic phases of the intoxication. At the end of the 60-day period of TAM-treatment, the radioactivity incorporated into fatty acids was significantly lowered. These data showed that the alterations in hepatic lipogenesis observed during TAM administration are related to changes in the activities of lipogenic enzymes and probably are a consequence of alterations in plasma insulin concentration. Disturbances in lipid metabolism should play an important role in the pathogenesis of liver damage and its physiological significance could involve metabolic changes in proliferative and neoplastic liver diseases.

Acetamides↗