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PubMed1999

Changes in hepatic nitrogen metabolism in isolated perfused liver during the development of thioacetamide-induced cirrhosis in rats.

Changes in hepatic nitrogen metabolism in isolated perfused liver were studied during the induction of experimental cirrhosis by thioacetamide in female Sprague-Dawley rats. Cirrhosis of the micronodular type developed during 12-week administration of thioacetamide. Despite an increase in food consumption for 4 weeks after the end of administration, the physiological changes characteristic of cirrhosis were maintained. The rate of urea excretion per unit liver weight was significantly decreased compared with pair-fed control rats both during and after thioacetamide treatment. During 4 weeks of thioacetamide treatment, the rate of urea production in perfused liver from a combination of 0.25 mM NH4Cl and 1 mM glutamine decreased slightly, without a decrease in the maximum rate of urea production from 10 mM NH4Cl. In cirrhotic rats, the rate of urea production in perfused liver from NH4Cl and/or glutamine decreased, with a decrease in the maximum rate of urea production. The Km of ureagenesis for NH3 was unchanged in cirrhotic livers. During 4 weeks of thioacetamide treatment, glutamate dehydrogenase activity decreased, but the thioacetamide-induced cirrhotic state had no effect on glutamate dehydrogenase or glutaminase activity. Glutamine synthetase activity was decreased in rats treated with thioacetamide for 4 or 12 weeks. These results are consistent with the hypothesis that the capacity for urea production from NH3 and amino acids is decreased in the development of cirrhosis.

Alanine Transaminase↗
PubMed1995

Hepatocellular regeneration: key to thioacetamide autoprotection.

Low doses of thioacetamide stimulate cell division and tissue repair in the liver. The objective of this study was to develop an autoprotection model for thioacetamide and investigate if a low dose of thioacetamide (50 mg/kg orally) protects against lethality of a subsequently administered lethal dose (400 mg/kg orally) of the same compound. The extent of cell division was investigated to test if autoprotection results from augmented tissue repair and recovery from injury rather than decreased injury itself. After a single administration of the protective dose of thioacetamide, hepatocellular nuclear DNA synthesis as measured by 3H-thymidine incorporation into hepatocellular nuclear DNA peaked at 36 hr indicating maximum level of S-phase stimulation. Pretreatment with the antimitotic colchicine abolished autoprotection and this was associated with a significantly decreased 3H-thymidine incorporation. Preadministration of the protective dose of thioacetamide did not result in an altered infliction of injury from the subsequently administered lethal dose. Colchicine intervention in the autoprotected group resulted in injury that followed a pattern similar to the group that received the high dose alone, ultimately resulting in animal death. These findings suggest that cell division stimulated by the protective low dose of thioacetamide is the critical mechanism in thioacetamide autoprotection.

Administration, Oral↗
PubMed1989

Thioacetamide- and carbon tetrachloride-induced liver cirrhosis.

Two methods of inducing liver cirrhosis in the rat were studied. Intragastric administration of CCl4 for 16 weeks according to Proctor and Chatamra was compared to the administration of thioacetamide in the drinking water (0.3 g/l) for the same period. CCl4 administration induced micronodular cirrhosis in 6/8 animals with a 27% mortality. Thioacetamide induced cirrhosis in 6/8 animals without mortality. The histologic pictures differed somewhat in that the CCl4 group exhibited more necrosis and cellular swelling while the thioacetamide group had more nuclear atypias and proliferation. Biochemically both groups had elevated plasma levels of aspartate aminotransferase. The lysosomal enzyme beta-hexosaminidase (beta-NAG) showed a transient increase in the thioacetamide animals, while beta-glucuronidase decreased. CCl4-induced cirrhosis led to an increase in beta-NAG. Plasma zinc decreased in both groups as well as liver zinc content in the CCl4 group, while there was a continuous elevation of liver zinc in the thioacetamide group. We conclude that oral administration of thioacetamide is a simple and reliable method of inducing experimental liver cirrhosis. The differences in histological appearances and some biochemical parameters may be caused by the different mechanisms of action of thioacetamide and CCl4.

Acetamides↗
PubMed1986

Effect of thioacetamide on the incorporation of [3H]-thymidine into DNA of 13 tissues and on the mitotic index of the corneal epithelium of BD2F1 in male mice while taking into consideration circadian variation.

An investigation was done to assess the effect of a single intraperitoneal (ip) injection of thioacetamide on the incorporation of [3H]TdR into DNA of 13 different tissues and on the mitotic index of the corneal epithelium of mice. Seven-week-old CD2F1 mice, who had been standardized to 12 hours (hr) of light alternating with 12 hr of darkness, and fed ad libitum were used. The experimental design took into consideration the circadian variation that characterizes cell proliferation in all of the tissues studied. This was done by killing subgroups of seven animals every 6 hr for 96 hr. Thirty minutes prior to killing all mice were injected ip with 25 mu Ci of [3H]-thymidine and its incorporation into DNA was determined. The tissues of all thioacetamide and saline treated mice showed marked circadian variation in DNA synthesis. Thioacetamide treatment brought about significant (P less than 0.05) stimulation of DNA synthesis in the liver and kidney thus confirming, but extending an earlier finding. Moreover, the data showed for the first time that DNA synthesis in the bone marrow and spleen and colon were markedly statistically significantly stimulated at specific times after treatment. Synthesis of DNA in the thymus, lung, testes, tongue, esophagus, duodenum, rectum and the mitotic index in the corneal epithelium were not statistically significantly altered by thioacetamide treatment. A preliminary study also was carried out to explore what effect multiple treatment with epidermal growth factor (EGF) had on DNA synthesis in thioacetamide treated mice. Mice were killed 36 hr after thioacetamide treatment, but were treated with EGF which began 15 hr after the thioacetamide was administered and this was repeated at 18, 21 and 24 hr (50 micrograms/mouse/treatment). Under the conditions of this study EGF significantly (P less than 0.05) depressed DNA synthesis 76% in the liver, 64% in the thymus, 22% in the spleen, 30% in the duodenum and 24% in the esophagus. A histological analysis of the livers of four EGF treated and four non-EGF treated mice was done, but no consistent differences in terms of necrosis, inflammation or regeneration were observed between the two groups.

Acetamides↗
PubMed1992

Isoenzymes of carbohydrate metabolism in primary cultures of hepatocytes from thioacetamide-induced rat liver necrosis: responses to growth factors.

Hepatocytes isolated from the liver of rats after a necrotizing dose of thioacetamide (6.6 mmol/kg) were used to study the postnecrotic process of liver regeneration. Flow cytometry analysis revealed populations of dedifferentiated hepatocytes exhibiting physical properties (size and fluorescence emission at 530 nm) similar to those found in fetal (22 days old) liver cells. The percentage of these cells increased progressively from 24 to 48 and 72 hr after thioacetamide administration. In primary cultures of hepatocytes the effects of phorbol 12-myristate 13-acetate, bombesin and insulin were investigated on the 6-phosphofructo 2-kinase/fructose 2,6 bisphosphate system. Bombesin and insulin stimulated 6-phosphofructo 2-kinase activity and fructose 2,6-bisphosphate content both in control and in thioacetamide-treated hepatocytes. However, phorbol 12-myristate 13-acetate stimulated 6-phosphofructo 2-kinase activity and increased fructose 2,6-bisphosphate concentration in thioacetamide-treated liver cells, whereas no similar response was found in hepatocytes from control rats. The response of postnecrotic thioacetamide-treated hepatocytes to phorbol 12-myristate 13-acetate was similar to that obtained from 22-day-old fetal liver cells, which reveals that different methods might control fructose 2,6-bisphosphate content and therefore the mechanisms of glycolysis and gluconeogenesis at this regulatory step. The lack of response to glucagon of glycogen phosphorylase a and 6-phosphofructo 2-kinase from thioacetamide-treated hepatocytes may indicate that the expression of specific enzymes of carbohydrate metabolism undergoes transitions to less-differentiated isoenzymatic forms. Moreover, the isoenzyme pattern of hexokinases elicits a complete disturbance in glucokinase and hexokinases activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

Rapid development of hyperplastic nodules and cirrhosis in the liver of rats treated concurrently with thioacetamide and the pyrrolizidine alkaloid lasiocarpine.

Pyrrolizidine alkaloids have long been considered to be hepatotoxic in man as well as in grazing animals. To investigate the effect of liver cell division induced by thioacetamide on the hepatic changes induced by these alkaloids, rats were treated concurrently with thioacetamide and the pyrrolizidine alkaloid lasiocarpine. Thioacetamide was given intraperitoneally in a dose of 50 mg/kg b. wt twice weekly and lasiocarpine was administered in the diet at a concentration of 50 ppm. At 15 weeks, the combination of thioacetamide and lasiocarpine produced numerous grossly visible grey nodules in livers of 26 of 30 rats. Microscopically, these livers revealed a severe degree of postnecrotic cirrhosis and numerous hyperplastic nodules. The cells in most nodules were arranged in solid sheets or in a trabecular pattern and shown atypia, mitosis and hyperchromasia. In contrast, there was no evidence of cirrhosis or nodule formation in livers of animals treated with either lasiocarpine or thioacetamide alone. The rapid development of liver lesions in rats treated simultaneously with low doses of lasiocarpine and thioacetamide suggests that cell proliferation accentuates the development of neoplasia.ł

Acetamides↗
PubMed1981

Microsomal activation of thioacetamide-S-oxide to a metabolite(s) that covalently binds to calf thymus DNA and other polynucleotides.

In the presence of NADPH liver microsomes isolated from phenobarbital-pretreated rats catalyze the conversion of [3H]thioacetamide-S-oxide to a reactive intermediate(s) which covalently binds to calf thymus DNA, calf liver RNA, polyguanylic acid (poly(G)) and polyadenylic acid (poly(A)). The highest level of binding of radioactivity was obtained with poly(G), followed by poly(A), RNA and DNA. The incorporation of radioactivity into DNA was linear for 30 min and there was a requirement for NADPH for time-dependent covalent binding to occur. Performing the microsomal incubations in an atmosphere of 80% CO/20% O2 or adding partially purified anti cytochrome P-450 immune serum to the microsomal incubations inhibited the total metabolism of thioacetamide-S-oxide and had a small, but insignificant, inhibitory effect on binding of radioactivity to calf thymus DNA. Using a reconstituted monooxygenase system containing cytochrome P-450 purified from phenobarbital-treated rats we were unable to detect any metabolism of thioacetamide-S-oxide. Only background levels of radio-activity were incorporated into calf thymus DNA when microsomes isolated from phenobarbital-treated rats were incubated with [3H]thioacetamide in the presence of NADPH. These results suggest that thioacetamide-S-oxide is an obligatory intermediate in the metabolic activation of thioacetamide to a reactive metabolite(s) which binds to calf thumus DNA.

Acetamides↗
PubMed1996

Serum amino acid changes in rats with thioacetamide-induced liver cirrhosis.

To date, no attempt has been made to study alterations occurring in the amino acid profile in chronic models of thioacetamide-induced liver cirrhosis. In this work, changes in serum amino acids and proteins in rats with thioacetamide-induced liver cirrhosis are reported, together with changes in enzyme activities in the liver and serum. Seventeen female Wistar rats were used. Eight rats were given 300 mg thioacetamide/l in drinking water for 4 months and nine rats were given water ad libitum during the same time-period. Significant increases in glycine, alanine, serine, methionine, glutamate, ornithine, phenylalanine, tyrosine, histidine and proline were observed in rats with the resulting experimental liver cirrhosis. Threonine, taurine, glutamine, lysine and citrulline tended to increase while isoleucine, leucine, aspartate, arginine and tryptophan tended to decrease. Total and nonessential amino acids increased significantly in cirrhotic animals. Total essential and aromatic amino acids tended to increase in the thioacetamide-treated group, whereas branched chain amino acids tended to decrease in the same group. Regarding serum proteins, a decrease in albumin concentration in the thioacetamide-treated animals was the only change detected. The liver enzyme activities under observation (aspartate and alanine aminotransferases, glutamate dehydrogenase and threonine deaminase) were lower in the thioacetamide group. Decreases were significant for both transaminases and threonine deaminase. Results for serum activities showed that transaminases did not change in thioacetamide-treated rats in comparison with controls. In contrast, alkaline phosphatase rose dramatically in cirrhotic rats. We conclude that the serum amino acid pattern in this chronic model of liver cirrhosis resembles in part that of the corresponding human disease.

Administration, Oral↗
PubMed2004

Effect of a load of Vitamin A after acute thioacetamide intoxication on dolichol, dolichol isoprenoids and retinol content in isolated rat liver cells.

This study examines how treatment with a single dose of thioacetamide, a known experimental hepatotoxin, alters the content of dolichol, dolichol isoprene units and retinol in isolated rat parenchymal and non-parenchymal liver cells at different times and when the animals are supplemented with Vitamin A. Thioacetamide (300 mg/kg i.p.) was administered in a single injection to rats, sacrificed at intervals of 0.5, 1, 2, 3, 4, 15 and 30 days. Rats supplemented, following thioacetamide, with Vitamin A, 3 days before sacrifice showed increased mortality and cellular necrosis on the third and fourth days. Parameters indicating tissue necrosis returned to normal values in surviving animals. Dolichol and retinol content showed a variable, reversible decrease, with normal levels being restored in 15-30 days. After Vitamin A, dolichol content only in hepatic stellate cells (HSC) was lower then the controls 3 and 4 days after thioacetamide treatment, in parallel with the decrease of retinol storage. The percentage of dolichol-18 is not modified by thioacetamide alone. When supplemented with Vitamin A the percentage of dolichol-18 always decreased after thioacetamide, showing that damage was still present. Mechanisms that might be operative in liver cells are briefly discussed. This approach would provide an indication to investigate how the length of the dolichol chain is determined.

Animals↗
PubMed2003

Depletion of Kupffer cell function by gadolinium chloride attenuates thioacetamide-induced hepatotoxicity. Expression of metallothionein and HSP70.

Kupffer cell function plays an important role in drug-induced liver injury. Thus, gadolinium chloride (GD), by selectively inactivating Kupffer cells, can alleviate drug-induced hepatotoxicity. The effect of GD was studied in reference to metallothionein and heat shock proteins expression in an in vivo model of liver necrosis induced by thioacetamide. Rats, pre-treated or not with GD (0.1 mmol/kg), were intraperitoneally injected with thioacetamide (6.6 mmol/kg), and samples of blood and liver were obtained at 0, 12, 24, 48, 72 and 96 hr. Parameters related to liver damage, Kupffer cell function, microsomal FAD monooxygenase activity, oxidative stress, and the expression of metallothionein and HSP70 were determined. GD significantly reduced serum myeloperoxidase activity and serum concentration of TNF alpha and IL-6, increased by thioacetamide. The extent of necrosis, the degree of oxidative stress and lipoperoxidation and microsomal FAD monooxygenase activity were significantly diminished by GD. The effect of GD induced noticeable changes in the expression of both metallothionein and HSP70, compared to those induced by thioacetamide. We conclude that GD pre-treatment reduces thioacetamide-induced liver injury and enhances the expression of metallothionein and HSP70. This effect, parallel to reduced levels of serum cytokines and myeloperoxidase activity, demonstrates that Kupffer cells are involved in thioacetamide-induced liver injury, the degree of contribution being approximately 50%.

Animals↗
PubMed1998

Necrogenic and regenerative responses of liver of newly weaned rats against a sublethal dose of thioacetamide.

The hepatocellular necrogenic and regenerative responses of newly weaned rats (21 days old) to a sublethal dose of thioacetamide (6.6 mmol kg-1) were studied in comparison to adult (6-month old rats), in terms of liver injury, antioxidant defense systems and cell proliferation. Hepatocellular necrosis, detected by serum aspartate aminotransferase, was less severe in newly weaned rats than in adult animals and was parallel to previous changes in the activity of microsomal FAD monooxygenase system responsible for thioacetamide biotransformation. Liver damage in hepatocytes from newly weaned rats was also detected by the decreased levels of glutathione and protein thiol groups (47%, p < 0.001 and 52%, p < 0.001 vs. untreated, respectively) and by the enhanced malondialdehyde production (334%, p < 0.001) and glutathione S-transferase activity (384%, p < 0.001). No significant differences were detected in these values when compared to adults. Changes in cytosolic and mitochondrial superoxide dismutase and catalase activities in hepatocytes from newly weaned rats at 24 h, following thioacetamide (49%, p < 0.001; 50% and 53%, p < 0.001 vs. untreated, respectively), were less severe against those in adult hepatocytes at 48 h of intoxication, and the increases in glutathione peroxidase and glutathione reductase activities were significantly lowered: 25% (p < 0.001) and 41% (p < 0.001), respectively. Post-necrotic DNA synthesis in hepatocytes from newly weaned rats peaked at 48 h of intoxication, while in adults a more intense peak appeared at 72 h preceded by a sharp decrease in tetraploid population. These differences indicate that the lower necrogenic response against the same dose of thioacetamide in newly weaned rats may be due to the lower rate of thioacetamide biotransformation and to the earlier onset of cell division. Accordingly, the growing liver from newly weaned rats presents advantages against the necrogenic aggression of thioacetamide, first, because the diminished activity of its specific microsomal detoxification system, and second because the earlier increase in the proliferative response prevents the progression of injury permitting an earlier restoration of liver function.

Animals↗
PubMed1993

Microsomal sphingomyelin accumulation in thioacetamide-injured regenerating rat liver: involvement of sphingomyelin synthase activity.

The purpose of this work was to determine whether alterations in the lipid composition of rat liver microsomal membranes existed during thioacetamide-induced injury prior to the development of hepatic cancer and biochemical mechanisms involved. Rats were injected intraperitoneally with (50 mg/kg body wt per day) thioacetamide or diluent for 8 days. Liver homogenates and microsomal membranes from liver homogenates were obtained. Incorporation of [32P]orthophosphate into whole liver lipids and hepatic microsomal lipids was evaluated 75 min after isotope administration. These determinations were made after two separate periods of treatment (3 and 8 days). Activity of sphingomyelin synthase was assayed in rat liver homogenates as well as in the purified microsomal fractions. Results demonstrated a maintenance of liver and hepatic microsomal contents of phosphatidylcholine during thioacetamide-induced injury even when the biosynthesis of this glycerophospholipid in both liver and their microsomal fractions appeared decreased. Also observed was a considerable increase of microsomal sphingomyelin, as well as an increased hepatic biosynthesis of sphingomyelin caused by thioacetamide treatment. The microsomal sphingomyelin/phosphatidylcholine radioactivity ratio significantly increased. Sphingomyelin synthase activity in liver homogenate appeared stimulated. In conclusion, our data are consistent with a thioacetamide-induced increase in microsomal sphingomyelin by a stimulation of sphingomyelin synthase. Based on this and previous studies, accumulation of sphingomyelin in the microsomal purified fraction is associated with the number of thioacetamide doses and is an early event clearly detected prior to tumoral characteristics of hepatocytes.

Animals↗
PubMed1993

Cerebral metabolic and histological effects of thioacetamide-induced liver failure.

Acute liver failure was induced in rats by successive administrations of thioacetamide over 3 days. At progressing stages of hepatic encephalopathy (HE), brains were fixed with microwave irradiation for analysis of metabolite levels or with formaldehyde for histopathological analysis. Metabolite levels were determined using 1H-nuclear magnetic resonance spectroscopy of perchloric acid extracts of the frontal cortex, parietal or occipital cortex, hippocampus, striatum, brain stem, and cerebellum. After thioacetamide treatment, thioacetamide and its metabolites were detected in the brains at levels that did not correlate with the stage of HE. No changes were observed in the levels of N-acetylaspartate, alanine, gamma-aminobutyric acid, aspartate, or inositol in any brain region after thioacetamide treatment. HE was accompanied by elevated glutamine, glucose, and lactate throughout the brain. At all stages of HE, taurine was decreased in the neocortex and hippocampus, and glutamate and choline compounds were decreased in the frontal cortex. None of the metabolite changes showed progression with the stage of HE. Progressing HE was accompanied by increasing neuronal injury in layer III of the neocortex, in the Purkinje cells of the cerebellum, and in the hippocampus, particularly in the CA4 sector. The similarity of this distribution of injury to that associated with excitotoxic injury suggests that metabolic abnormalities after acute hepatic failure may give rise to adverse effects at excitatory (glutamatergic) neuronal receptors, leading to neuronal injury and clinical symptoms of progressing encephalopathy in this model. However, neuronal injury and the presence of thioacetamide and its metabolites in the brain raise questions about the validity of thioacetamide-induced liver failure as a model for clinical HE.

Animals↗
PubMed2000

Antihepatotoxic activity of Rosmarinus tomentosus in a model of acute hepatic damage induced by thioacetamide.

R. tomentosus is a vegetal species closely related to the culinary rosemary (R. officinalis), a plant reported to contain antihepatotoxic agents. A dried ethanol extract of the aerial parts of Rosmarinus tomentosus (Lamiaceae) and its major fraction separated by column chromatography (fraction F19) were evaluated for antihepatotoxic activity in rats with acute liver damage induced by a single oral dose of thioacetamide. Silymarin was used as a reference antihepatotoxic substance. Pre-treatment with R. tomentosus ethanol extract, fraction F19 or silymarin significantly reduced the impact of thioacetamide toxicity on plasma protein and urea levels as well as on plasma aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and gamma-glutamyl transpeptidase activities compared with thioacetamide-treated animals (group T). Pre-treatment with R. tomentosus ethanol extract significantly reduced the impact of thioacetamide damage on alkaline phosphatase and gamma-glutamyl transpeptidase activities compared with group T. Silymarin administration significantly reduced alkaline phosphatase and gamma-glutamyl transpeptidase activities compared with group T. Fraction F19 administration reduced only alkaline phosphatase activity compared with group T. According to these data, R. tomentosus extract shows promising antihepatotoxic activity, suggesting the need to isolate the chemical principles responsible for this activity and to study this activity in a model of thioacetamide-induced cirrhosis.

Animals↗
PubMed1993

Relationship between genomic DNA ploidy and parameters of liver damage during necrosis and regeneration induced by thioacetamide.

Thioacetamide proved to be a potent necrogenic agent when a single dose of 6.6 mmol/kg was administered intraperitoneally to rats. Its necrogenic ability was assessed on the basis of morphological and biochemical changes. The injury of centrilobular hepatocytes showed a peak of cell death 24 hr after thioacetamide administration; it was followed immediately by the regenerative response. Parallel increases of serum aminotransferases, isocitrate dehydrogenase and gamma-glutamyl transferase activities were observed. Severe liver damage was also evident at 24 hr on the basis of glutathione depletion (29% of control), malondialdehyde production (169%), cytochrome P-450 level decrease (26%) and increased activity of glutathione S-transferase (160%). We checked the regenerative response by determining nuclear DNA content in isolated hepatocytes 0, 6, 12, 18, 24, 36, 48 and 72 hr after thioacetamide administration. Changes in DNA cell distribution between G0-G1, S and G2 + M phases of the cell cycle were observed. The sharp decrease in the percentage of the tetraploid cell population (G2 + M phases) and the abrupt increase of the S-phase cells at 36 and 48 hr suggest transition from adult to fetal in hepatocyte populations obtained 24 and 36 hr after thioacetamide treatment. At 72 hr of treatment, hepatocyte populations showed recovery to adult state. In the shift from the adult to fetal, registered at 24, 36 and 48 hr after thioacetamide administration, mitosis seemed to precede the synthesis of DNA.

Animals↗
PubMed1989

Chronic liver injury by thioacetamide and promotion of hepatic carcinogenesis.

To verify whether a mild, but prolonged liver injury by chemicals needing bioactivation causes both hepatic cirrhosis and the appearance of hepatocyte nodules and tumors (providing the liver has been exposed previously to initiating stimuli), diethylnitrosamine-initiated and uninitiated rats were administered thioacetamide at low dose (250 mg/l drinking water) for 6 months. Hepatocyte nodule incidence as well as changes in the drug-metabolizing system were followed at monthly intervals. In the uninitiated rats a micronodular liver cirrhosis slowly developed upon thioacetamide chronic administration; a few hepatocyte focal lesions of small size were seen from the 3rd month onward. By contrast in the diethylnitrosamine-initiated thioacetamide-treated rats the liver was macronodular because of the appearance and growth of many hepatocyte nodules; some hepatomas were also seen. During thioacetamide administration both uninitiated and diethylnitrosamine-initiated rats underwent a progressive decrease of the cytochrome P-450 liver content as well as of the activity of aminopyrine N-demethylase, ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase. On the other hand, most components of the phase II of the drug-metabolizing system were markedly enhanced. In conclusion, chronic administration of thioacetamide at low doses provided strong promoting stimuli for previously initiated hepatocytes.

Acetamides↗
PubMed1990

Effect of acute thioacetamide administration on rat brain phospholipid metabolism.

Brain phospholipid composition and the [32P]orthophosphate incorporation into brain phospholipids of control and rats treated for 3 days with thioacetamide were studied. Brain phospholipid content, phosphatidylcholine, phosphatidylethanolamine, lysolecithin and phosphatidic acid did not show any significant change by the effect of thioacetamide. In contrast, thioacetamide induced a significant decrease in the levels of phosphatidylserine, sphingomyelin, phosphatidylinositol and diphosphatidylglycerol. After 75 minutes of intraperitoneal label injection, specific radioactivity of all the above phospholipids with the exception of phosphatidylethanolamine and phosphatidylcholine significantly increased. After 13 hours of isotope administration the specific radioactivity of almost all studied phospholipid classes was elevated, except for phosphatidic acid, the specific radioactivity of which did not change and for diphosphatidylglycerol which showed a decrease in specific radioactivity. These results suggest that under thioacetamide treatment brain phospholipids undergo metabolic transformations that may contribute to the hepatic encephalopathy induced by thioacetamide.

Alanine Transaminase↗
PubMed2004

Pretreatment with 1,8-cineole potentiates thioacetamide-induced hepatotoxicity and immunosuppression.

The effect of 1,8-cineole on cytochrome P450 (CYP) expression was investigated in male Sprague Dawley rats and female BALB/c mice. When rats were treated orally with 200, 400 and 800 mg/kg of 1,8-cineole for 3 consecutive days, the liver microsomal activities of benzyloxyresorufin- and pentoxyresorufin-omicron-dealkylases and erythromycin N-demethylase were dose-dependently induced. The Western immunoblotting analyses clearly indicated the induction of CYP 2B1/2 and CYP 3A1/2 proteins by 1,8-cineole. At the doses employed, 1,8-cineole did not cause toxicity, including hepatotoxicity. Subsequently, 1,8-cineole was applied to study the role of metabolic activation in thioacetamide-induced hepatotoxicity and/or immunotoxicity in animal models. To investigate a possible role of metabolic activation by CYP enzymes in thioacetamide-induced hepatotoxicity, rats were pre-treated with 800 mg/kg of 1 ,8-cineole for 3 days, followed by a single intraperitoneal treatment with 50 and 100 mg/kg of thioacetamide in saline. 24 h later, thioacetamide-induced hepatotoxicity was significantly potentiated by the pretreatment with 1,8-cineole. When female BALB/c mice were pretreated with 800 mg/kg of 1,8-cineole for 3 days, followed by a single intraperitoneal treatment with 100 mg/kg of thioacetamide, the antibody response to sheep red blood cells was significantly potentiated. In addition, the liver microsomal activities of CYP 2B enzymes were significantly induced by 1,8-cineole as in rats. Taken together, our results indicated that 1,8-cineole might be a useful CYP modulator in investigating the possible role of metabolic activation in chemical-induced hepatotoxicity and immunotoxicity.

Alanine Transaminase↗