Thioacetamide-induced hepatic necrosis. II. Pharmacokinetics of thioacetamide and thioacetamide-S-oxide in the rat.
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Acetamides↗
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Inhibition of delta-aminolevulinic acid synthetase by thioacetamide and thioacetamide-S-oxide.
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5-Aminolevulinate Synthetase↗
Metabolism of thioacetamide and thioacetamide S-oxide by rat liver microsomes.
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Acetamides↗
Thioacetamide-induced hepatic necrosis. I. Involvement of the mixed-function oxidase enzyme system.
Metabolic activation of thioacetamide (CH3CSNH2) to a toxic metabolite which is responsible for its hepatotoxicity and/or its carcinogenicity has been proposed by a number of investigators. In this investigation thioacetamide and one of its metabolites, thioacetamide sulfine (CH3CSONH2), have been compared for their ability to inhibit hepatic mixed-function oxidase enzymes as well as their ability to induce hepatic necrosis. Thioacetamide sulfine was found to decrease aminopyrine N-demethylation and aniline hydroxylation at a lower dose and at an earlier time after administration than was the case with thioacetamide. In addition, at all doses examined, thioacetamide sulfine produced a more severe centrilobular hepatic necrosis than equivalent doses of thioacetamide. To determine whether the hepatic mixed-function oxidase enzyme system was involved in the biotransformation of thioacetamide and/or thioacetamide sulfine to a hepatotoxic compound(s), the severity of liver damage was examined after the administration of an inducer or inhibitors of hepatic mixed-function oxidase enzyme activity. Phenobarbital pretreatment potentiated the hepatic necrosis produced by both thioacetamide and thioacetamide sulfine. In contrast, pyrazole, SKF 525-A, and cobaltous chloride protected against the hepatic necrosis caused by thioacetamide and thioacetamide sulfine. These data suggest that both thioacetamide and thioacetamide sulfine are activated by hepatic mixed-function oxidase enzymes to a hepatotoxic compound(s). These data also suggest that the hepatotoxicity may be mediated by its metabolism to thioacetamide sulfine which, in turn, is metabolized to an ultimate toxic metabolite.
Acetamides↗
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↗
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↗
Ultrastructural alterations and modifications of nuclear RNA of rat liver by the combined action of thioacetamide and aflatoxin.
When aflatoxin is administered to thioacetamide-treated rats, the synthesis of nuclear RNA not only stops but the RNA that had accumulated in the nuclei by thioacetamide action disappears, probably by degradation "in situ" as none appears in the cytoplasm. Morphologically, the lesions provoked by aflatoxin add to those caused by thioacetamide. In the gigantic nucleoli that develop upon exposure to thioacetamide, aflatoxin provokes atypical segregations that result in the formation of larger and larger spaces in the nucleoli.
Acetamides↗
Hepatocyte population dynamics during hydrocortisone and thioacetamide treatment.
The orderly organization in a number of discrete classes of weight persists in the hepatocytes during acute and chronic poisoning with thioacetamide and during a prolonged treatment with hydrocortisone, though many striking cytological and structural changes occur in the liver. The number of hepatocyte classes decreases under hydrocortisone treatment and during acute and chronic thioacetamide poisoning, and increases during recovery after acute thioacetamide poisoning and during the late phases of chronic thioacetamide poisoning. This is due to decrements and increments in dry mass of the hepatocytes, which occur by steps, through repeated losses and additions of a constant amount of solids substantially corresponding to the class period. Such a mechanism is similar to that acting in the hepatocyte atrophy due to starvation and in the hepatocyte enlargement occurring during postnatal development. Therefore, the increment and the decrement in dry mass by defined steps takes place in the hepatocytes in both physiological and pathological conditions.
Acetamides↗
[The thioacetamide-poisoned rat as an animal experimental model for endocrinological studies of estrogen metabolism in chronic liver injury)].
Liver microsomes of rats poisoned with thioacetamide show a significant reduction of cytochrome P-450. Consequently, oxidative reactions of drug metabolism and the estrogen 2-hydroxylase are diminished. Enhancement of microsomal transformation of estradiol to estrone and 16alpha-hydroxyestrone is observed after treatment of rats with thioacetamide, due to diminished metabolism of estradiol by the alternative oxidation at C-2. Estriol formation is reduced by thioacetamide pretreatment. These changes in estrogen breakdown closely correlate with those observed in humans suffering from cirrhosis of the liver. It is concluded that the thioacetamide poisoned rat should be an experimental model suitable for studying estrogen metabolism in liver injury.
Acetamides↗
Stimulation of hepatocellular proliferation by a serum factor from thioacetamide-treated rats.
Rats treated with thioacetamide undergo hepatocellular proliferation reminscent of liver regeneration following partial hepatectomy. 36 h after administration of 50 mg thioacetamide/kg body weight to rats, [3H]thymidine incorporation into hepatic DNA reaches a peak of 78-10(3) dpm/mg DNA compared to a control of 3.2-10(3) dpm/mg DNA. Serum obtained from 6 to 48 h after administration of thioacetamide to rats stimulated hepatic but not kidney DNA synthesis in mice and rats. Autoradiography revealed an increase in the incorporation of labelled thymidine into the nuclei of mouse hepatocytes. The mitotic index of the liver was also increased. The serum factor stimulating these changes in the liver was non-dialyzable and heat stable. These results indicate that thioacetamide induced liver injury results in a humoral factor which stimulates DNA synthesis in rat and mouse identified in the serum from partially hepatectomized rats.
Acetamides↗
Comparative karyometric studies on small pseudolobuli and hepatomas in thioacetamide induced liver cirrhosis.
In the tumorous phase of TAA-induced cirrhosis of the liver comparative studies on the mitotic index, on the frequency of binucleated liver cells and on nuclear volume showed approximately similar values in the small pseudolobuli and in several hepatomas. Obviously "minimum deviation hepatomas" had developed. Decrease of ploidy characteristic for hepatomas was observed. In thioacetamide hepatomas the phenomenon of quadrupling of the cell nuclei due to dysfunctional nuclear edema occurred whereas the normal nuclei of liver cells can only double in volume in all phases of thioacetamide-intoxication. Particular karyometric aspects of the nuclear-nucleolar metabolism of hepatoma cells following thioacetamide intoxication are discussed.
Animals↗
[Time course of thioacetamide-induced changes in estrogen metabolism in the rat liver].
Rats have been treated for 6 weeks with thioacetamide (0.1% in drinking water). The biochemical changes in liver microsomal metabolism of estradiol which are similar to those observed in human liver cirrhosis become already apparent after one week of treatment. These are diminishment of hepatic microsomal cytochromes P-450 and b5, comparable decrease of 2-hydroxylation and increase of formation of estrone from estradiol. The alterations of estrogen metabolism are reversible within two weeks after ending thioacetamide treatment. These data correspond to the already well established histological response of rat liver to thioacetamide, and its reversibility.
Acetamides↗
[The behavior of albumin in acute and chronic liver diseases. I. The behavior of albumin during the development of rat thioacetamide cirrhosis].
The behaviour of albumin during the development of chronic progressing liver damages was investigated on the model of the thioacetamide cirrhosis in Wistar-rats. Simultaneous estimations of the albumin concentrations in extractable liver protein and in the serum as well as accompanying measurements of the total protein and of the transaminases SGOT and SGPT in the serum allow a complex judgment. The albumin concentration in the liver significantly decreased after 4 and 8 weeks and reached highly normal values in fully developed cirrhosis. In each case the serum level changed in the same sense, but less expressed. The total protein in liver and serum showed an analogous course of the curve, whereas the albumin-total protein-quotient in the liver remained unchangedly low. The relative proportion of albumin in the serum did not show a diminution in every phase. The simultaneous decrease of albumin and total protein are explained as an expression of an inhibition of the synthesis due to destruction of protein-synthesizing subcellular structures. The normalisation of the serum levels and of the highly normal albumin contents despite the developed cirrhosis become understandable by the loss of efficiency of the foreign substance thioacetamide in consequence of structural and biochemical adaptation. The thioacetamide cirrhosis of the rat in the investigated phase despite the microscopically provable so-called degenerative parenchymal damages is accompained by parameters of the increased protein metabolism. The relative serum albumin content apparantly in the first place undergoes the oncotic pressure regulation and is not suited as the measure of a hepatocellular lesion. From the diagnostic point of view the reduction of the albumin concentrations seems to be of importance in the developmental phase to cirrhosis.
Alanine Transaminase↗
Changes in hepatic nuclei induced by acetamide and thioacetamide.
Rat liver nuclei were examined following intoxication with thioacetamide or acetamide. A prompt increase in nuclear size occurred with the administration of either agent. The acetamide-related change was evanescent and, by 16 hours, the nuclei did not differ from controls. Thioacetamide produced an acute enlargement during the first eight hours and a second, more prolonged increase during the next 24 hours. The enlargement noted by microscopy was also detectable in isolated nuclei by flow spectrometry. Chemical determinations on isolated nuclei appear to sample the same size population seen in situ. An increase in RNA content of thioacetamide-treated nuclei occurred during the late phase. The temporal sequence of physical and chemical change suggests that the initial increase in nuclear volume is not the result of retained macromolecular formation but may involve intracellular water and electrolyte shifts.
Acetamides↗
[Effect of liver damage by thioacetamide on microsomal aromatization of testosterone in rats (author's transl)].
Rat liver microsomes, NADPH-regenerating system, and 1beta, 2beta-3H-testosterone have been incubated in vitro. The loss of tritium from the steroid, associated with aromatization of testosterone, was linear with time for 20 min and required NADPH. Pre-treatment of the rats with thioacetamide raised the liberation of tritium from 1beta, 2beta-3H-testosterone. The results suggest that liver damage by thioacetamide in rats may give rise to increased aromatization of testosterone.
Acetamides↗
Mutagenic effects of thioacetamide in Drosophila melanogaster.
Thioacetamide, which is carcinogenic in mice and rats, has been reported as negative in Ames's test on Salmonella his- with and without liver microsomal fraction (S 9 mix). Tests on Drosophila reported here showed a significant increase in sex-linked recessive lethals after treatment with thioacetamide, both after injection and after feeding of males.
Acetamides↗
Effects of alpha-amanitin, cycloheximide, and thioacetamide on low molecular weight nuclear RNA.
Studies were made on the effects of alpha-amanitin, cycloheximide, and thioacetamide on synthesis and content of low molecular weight nuclear RNA. Cycloheximide, an inhibitor of protein synthesis and the synthesis of 45S pre-rRNA and 5S RNA, also inhibited synthesis of nuclear U1 and U3 RNAs. alpha-Amanitin, an inhibited the synthesis of U1 and U2 low molecular weight nuclear RNA. Thioacetamide, which induces nucleolar hypertrophy and increased nucleolar RNA polymerase activity, markedly increased synthesis of 5.8S RNA and U3 RNA. These results show that syntheses of individual low molecular weight nuclear (LMWN) RNAs are controlled by different regulatory mechanisms. In particular, there appears to be a specific relationship between U3 RNA and functional states of the nucleolus.
Acetamides↗
Induction of ovalbumin synthesis in immature chicks by actinomycin D and thioacetamide.
Actinomycin D and thioacetamide induced ovalbumin synthesis and increased serum progesterone concentrations in immature chicks. The increase in progesterone induced by the carcinogens actinomycin D and thioacetamide may account for the induction of ovalbumin synthesis.
Acetamides↗