Inhibition by 3'-methyl-4-dimethylamino-azobenzene of in vitro cell-free protein synthesis: possible involvement of an electrophilic metabolite.

In vitro addition of the hepatocarcinogen 3′-Me-DAB to a cell-free protein synthesizing system using PMS from rat liver resulted in a marked inhibition of [¹⁴C]leucine incorporation. The inhibitory effect was dependent on the carcinogen being preincubated in the system in the presence of NADP⁺. NADP⁺ alone caused a marked stimulation of [¹⁴C]leucine incorporation. Both xenobiotic metabolism and the 3′-Me-DAB inhibitory effect were decreased by Triton X-100 treatment of the PMS and increased by phenobarbitone pretreatment of the rats. The NADP⁺ stimulatory effect on protein synthesis was doubled by Triton X-100 treatment and decreased by phenobarbitone pretreatment. The results indicate that the effects of 3′-Me-DAB and NADP⁺ on protein synthesis may occur via independent mechanisms, and suggest that the 3′-Me-DAB effect is mediated by a metabolite. This metabolite appears to be electrophilic since in vitro addition of the nucleophiles GSH and l-cysteine decreased the inhibitory effect of 3′-Me-DAB on protein synthesis. There was no correlation between the inhibitory effect of a series of azo dyes (3′-Me-DAB, 2′-Me-DAB, 2-Me-DAB and DAB) on in vitro protein synthesis and their respective carcinogenic potencies.     

Inhibited initial rates of poly-uridylic acid-directed phenylalanine incorporation by free ribosomes from the liver of rats fed hepatocarcinogens.

Female Holtzman rats were fed diets containing 3′-methyl-4-dimethyl-aminoazobenzene (3′-Me-DAB) for 4 weeks; control rats were fed the basal diet. Free ribosomes and membrane-bound ribosomes were isolated from livers and initial rates of phenylalanine incorporation in vitro into proteins were determined both in the absence and presence of poly-uridylic acid (poly-U). Initial rates of protein synthesis by membrane-bound ribosomes were not detectably affected by 3′-Me-DAB ingestion. Although initial rates of free ribosomes from control rat livers were stimulated by poly-U additions, rates for free ribosomes from 3′-Me-DAB-fed rats were not appreciably changed by poly-U. Defective poly-U-directed phenylalanine incorporation by free ribosomes from rats fed 3′-Me-DAB: (a) was dependent upon time-on-diets; (b) was not an artifact associated with the method of isolating free ribosomes; (c) was not corrected by changing the magnesium level of reaction mixtures or by supplementing the levels of pH 5 precipitate fraction, elongation factors or initiation factors; and (d) was not due to a failure to bind poly-U. Feeding other hepatocarcinogens, viz. 4′-fluoro-DAB, 2-acetylaminofluorene, aflatoxin and thioacetamide, to female Holtsman rats of feeding any of these five hepatocarcinogens to male Fischer rats also led to the development of defective poly-U-directed phenylalanine incorporation by hepatic free ribosomes. Male Holtzman rats and female Fischer rats developed the defect more slowly, i.e. 8 weeks of feeding was necessary before the defect was detected with three of the five hepatocarcinogens. The possibility that defective poly-U-directed phenylalanine incorporation was due to a ribosomal alteration, and the possibility of a linkage between this phenomenon and the animal's risk for cancer were discussed.     

Acinar distribution of glutathione-dependent detoxifying enzymes. Low glutathione peroxidase activity in perivenous hepatocytes

The acinar distribution of glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G-6-PDH) was examined by analyzing periportal (p.p.) and perivenous (p.v.) rat hepatocytes selectively isolated by the digitonin-collagenase perfusion. The cytosolic GST activity was higher in p.v. cells, but the microsomal GST and cytosolic GR were found to be evenly distributed in the acinus. In contrast, the activity of both the Se-dependent GPx and the microsomal (Se-independent) GPx, as well as G-6-PDH, was much lower in the p.v. than in the p.p. cells. The heterogeneous distribution of GST, GPx and G-6-PDH was confirmed by analyzing liver perfusion effluents collected after ante- or retrograde digitonin infusion. The relatively low activities of GPx and G-6-PDH in the p.v. cells could partly explain the susceptibility of this region to chemical injury.     

Ameliorative effect of ajwain extract on hexachlorocyclohexane-induced lipid peroxidation in rat liver

Effect of ajwain extract on hexachlorocyclohexane-induced oxidative stress and toxicity in rats were investigated. Six groups of rats were maintained for 12 weeks as (1) Control; (2) HCH (300 mg/kg body weight) injected (3) 1% ajwain extract incorporated diet (4)1% ajwain extract incorporated diet + HCH (5) 2% ajwain extract incorporated diet and (6) 2% ajwain extract incorporated diet + HCH. Results revealed that HCH administration lead to an increase in hepatic lipid peroxidation associated with reduction in, levels of glutathione (GSH), activity of superoxide dismutase (SOD), catalase and glucose-6-phosphate dehydrogenase. Prefeeding of ajwain extract resulted in decreased hepatic levels of lipid peroxides and increased GSH, GSH-peroxidase, G-6-PDH, SOD, catalase and glutathione S-transferase (GST) activities. At the same time there was a significant reduction in hepatic levels of HCH-induced raise in lipid peroxides as a result of the prefeeding the extract. Prefeeding of ajwain extract at 1% level to rats injected with HCH reverted the significant changes in catalase, G-6-PDH, GST and -glutamyl transpeptidase. HCH-induced formation of micronuclei in femur bone marrow was also reduced significantly. It was concluded that HCH administration resulted in hepatic free radical stress, causing toxicity, which could be reduced by the dietary ajwain extract.     

Carbohydrate and lipid metabolism in rats after hypokinesia

Hypokinesia (diminished muscular activity) elicits several substantial alterations in carbohydrate and lipid metabolism of animals and man. The aim of this study was to examine certain parameters of carbohydrate and lipid metabolism in blood and tissues of 118 rats weighing 180-220 g, during a 90 days' exposure to hypokinesia (HK) and a 90-days' readaptation period (RP), that is, after the termination of HK. All of the rats were divided into experimental and control groups. The experimental group of rats were kept in small individual cages made of plexiglass and the control group of rats was placed under ordinary vivarium conditions. The rats were decapitated on the 90th day of HK and on the 15th, 30th, 60th and 90th days of the RP. Such indices were measured as glycogen (G), total lipid (TL), cholesterol (CH) and triglycerides (TG) in hepatic tissues and skeletal muscles, and glucose-6-phosphate-dehydrogenase (G-6-PDH) activity in the liver and fatty tissues. There were also assayed: blood serum, sugar, total cholesterol, alpha-cholesterol (alpha-CH), beta-cholesterol (beta-CH) lipoproteins, acetone bodies (AB) and free fatty acids (FFA). On the 90th day of HK the content of CH, FFA and AB increased, the value of sugar and TG decreased in blood, the amount of G decreased and the level of CH increased in the liver and skeletal muscles. On the 15th day of RP most of the parameters under study returned to normal. However, G-6-PDH in the liver and adipose tissue were elevated and remained higher till the 60th day of the RP.(ABSTRACT TRUNCATED AT 250 WORDS)     

醋酸棉酚长期给药的进一步观察

给成年雄性大鼠每日服醋酸棉酚10 mg/kg,每周服6天。服6个月后进行病理和组织化学观察。结果说明给醋酸棉酚大鼠各主要脏器(心、肝、脾、肺、肾、肾上腺)的形态都没有明显变化。组织化学观察说明,给棉酚大鼠的肝脏油红“O”染色、G-6-P酶、ATP酶、ALP酶、ACP酶、糖原、RNA和DNA肾脏G-6-PDH、油红“O”染色、ATP酶、ACP酶、ALP酶;肾上腺3β-甾体脱氢酶、油红“O”染色、苏丹黑染色等与对照组比较都没有明显差别。     

Organ- and species-specific properties of glucose-6-phosphate dehydrogenase and the effect of molsidomine

Glucose-6-phosphate dehydrogenase (G-6-PDH) is the key enzyme of the pentose phosphate cycle and therefore regulates the synthesis of the nucleic acid constituent ribose-5-phosphate. At the same time the enzyme is coupled to the synthesis of reduced glutathione (GSH) which detoxifies electrophilic molecules (radicals) in the organism. Activity and stability of G-6-PDH and the influence of SIN 1--the active metabolite of molsidomine (Corvaton)--dithiothreitol (DTT) and NADP on these parameters were studied in enzyme preparations from different organs of the rat (liver, ethmoturbinates, blood) and from blood of mouse, guinea pig, rabbit, dog and man. The highest activity of G-6-PDH was measured in rat ethmoturbinates (69.26 +/- 5.91 mU/mg protein/min), the lowest in human blood (2.99 +/- 0.18 mU/mg protein/min). G-6-PDH of rat ethmoturbinates and of rat and dog blood was unstable and nearly completely inhibited by SIN 1. The enzyme of rat liver and of human, mouse, guinea pig and rabbit blood was stable and not influenced by SIN 1. These organ-and species-specific findings are discussed with respect to the toxicological actions of SIN 1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of cadmium on hepatic and renal gluconeogenic enzymes in female rats

Earlier, we have reported that cadmium (Cd) induced gluconeogenesis in male rats. Since females are as much exposed to cadmium as are males, this study was conducted to determine Cd effects on gluconeogenesis in female rats. Adult female rats were injected intraperitoneally (i.p.) with Cd at dose levels of 0.25, 0.75 and 1.25 $\text{mg}\text{kg}$ body weight per day for 4 weeks. The controls received saline for the same length of time. Daily food consumption and body weight gain were recorded. At the end of 2 and 4 weeks, 4 rats from each group were killed. Extension of treatment with 1.25 mg Cd for 4 weeks resulted in extreme Cd toxicity killing all animals before the completion of full treatment period. There were no significant changes in total body weight gain and weights of liver and kidney due to Cd. Serum protein increased significantly in animals receiving 0.75 and 1.25 mg Cd for 4 and 2 weeks, whereas serum glucose increased only in animals injected with 1.25 mg Cd for 2 weeks. SGOT and SGPT were elevated (P < 0.01) in dose- and time-dependent fashion. Activities of three key gluconeogenic enzymes glucose-6-phosphatase (G-6-Pase), fructose-1,6-diphosphatase (FD-Pase), and phosphoenolpyruvate carboxykinase (PEPCK) in liver and kidney were induced significantly (P < 0.01) in animals injected with 0.75 mg for 2 and 4 weeks and 1.25 mg for 2 weeks, and these increases were dose- and time-related. These results suggest that Cd alters hepatic and renal gluconeogenesis in female rats also.     

Adaptive changes caused by intermittent styrene inhalation on xenobiotic biotransformation

Intermittent 11-week exposure to styrene by inhalation (300 ppm 6 hr/day, 5 days/week) enhanced the activities of both drug hydroxylating (ethoxycoumarin O-deethylase, cytochrome P-450) and conjugating (epoxide hydratase, UDP glucuronosyl-transferase) enzymes in the liver and kidneys of adult male rats. The increases in drug monooxygenation reached a peak within 2 weeks, whereas enhancement in UDP glucurono-syltransferase activity (p-nitrophenol as the aglycone) was observed only after 6 weeks. A dose-dependent depression of glutathione occurred after 4-days of exposure when measured 0.5 hr subsequent to the last exposure. The following morning (18 hr after exposure), the hepatic glutathione concentrations were slightly increased in styrene-exposed animals. Degenerative morphologic alterations were also observed in the parenchymal cells of the liver already after 2 weeks exposure to 300 ppm.     

Protective effect of cordycepin-enriched Cordyceps militaris on alcoholic hepatotoxicity in Sprague–Dawley rats

This study was to investigate the protective effect of cordycepin-enriched Cordyceps militaris against alcohol-induced hepatotoxicity in Sprague–Dawley rats. Alcohol-feeding rats were fed diets with Paecilomyces japonica as CPJ group, C. militaris as CCM group, cordycepin-enriched C. militaris as CCMα group at the 3% (w/w) level and silymarin at the 0.1% (w/w) level for 4 weeks. Alcohol administration resulted in a significant increase in the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GTP), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) and the levels of blood alcohol and acetaldehyde in serum. However, CCMα group markedly prevented from alcohol-induced elevation of these parameters in serum. CCMα group showed the increased both hepatic activities of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). Unlike the action of alcohol treatment on alcoholic fatty liver, CCMα group was also attenuated lipid droplet accumulation in the hepatocytes. Present study was also confirmed the beneficial roles of silymarin (hepatoprotective agent) against alcohol-induced liver injury in rats. Therefore, cordycepin-enriched C. militaris can be a promising candidate to prevent from alcohol-induced hepatotoxicity.     

Sulfasalazine prevents the increase in TGF-β, COX-2, nuclear NFκB translocation and fibrosis in CCl4-induced liver cirrhosis in the rat

It has been demonstrated that this sulfasalazine (SF) inhibits the nuclear factor κB (NFκB) pathway, which regulates important genes during inflammation and immune answer. The aim of this work was to evaluate the effects of SF on carbon tetrachloride (CCl(4))-induced liver fibrosis. We formed the following experimental groups of rats: controls, damage induced by chronic CCl(4) (0.4?g/kg, intraperitoneally, three times a week for 8 weeks) administration and CCl(4)?+?SF (100?mg/kg/day, postoperatively for 8 weeks) administration. We determined the activities of alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GTP), cyclooxygenase (COX)-1 and COX-2, lipid peroxidation, glutathione levels, collagen content, expression of transforming growth factor-β (TGF-β) and nuclear translocation of NFκB. SF was capable to inhibit the ALT and γ-GTP elevated levels induced with the CCl(4) administration. SF had antioxidant properties, prevented the lipid peroxidation and the imbalance of reduced and oxidized glutathione produced by CCl(4). Importantly, SF blocked the accumulation of collagen in the liver, the expression of TGF-β, the nuclear translocation of NFκB and the activity of COX-2, all induced with the administration of CCl(4) in the rat. These results show that SF has strong antifibrotic properties because of its antioxidant properties and its ability to prevent nuclear translocation of NFκB and consequently the expression of TGF-β and the activity of COX-2.     

磷,砷,四氯化碳肝损伤线粒体和微粒体乳酸脱氢酶同工酶的改变

本文对P4,NaAsO_2,CCl_4亚慢性肝损伤大鼠肝细胞线粒体,微粒体LDH同工酶进行聚丙烯酰胺凝胶电泳,光密度扫描定量,对其标志酶组化染色,微机图象定量分析,结果表明,三组动物肝小叶线粒体标志酶SDH活性均有下降,其中以CCl_4组SDH下降较迟.NaAsO_2组染毒第8wk可见线粒体LDH_5升高,染毒12wk LDH_(2,3)下降,LDH_5升高与对照组比较无显著性差异,但仍高于P_4组,各组间微粒体LDH同工酶和其标志酶G-6-P酶活性变化存在差异;P_4组微粒体LDH同工酶改变明显且较其他两组早。     

A comparative study of the efficacy of pharmacological agents in regulating the level of NADPH in the hepatocytes in an acute lesion]

Experiments on mice with acute toxic damage to the liver induced by thioacetamide (200 mg/kg) demonstrated inhibited activity of enzymes glucose-6-phosphate dehydrogenase (G-6-PDH), NADPH-dependent isocitrate dehydrogenase and malate dehydrogenase in the hepatocyte mitochondrial and microsomal-cytosol fractions. Pharmacotherapy with membranostabilizers and cytochrome P-450 inducers activated the enzymes under study, the degree of activation depended on agents used.     

Acute and subchronic toxicity studies of the new quinolone antibacterial agent irloxacin in rodents.

Irloxacin (6-fluorine-7-(pyrrol-1-yl)-1-ethyl-1, 4-dihydro-4-oxo-quinolone-3-carboxylic acid, CAS 91524-15-1), a new quinolone antibacterial agent, was administered as a single dose to rats and mice both by oral and intraperitoneal route in oder to study its acute toxicity. Its oral subchronic toxicity was also assessed by treating rats for 4 and 13 weeks. The results obtained showed that irloxacin was well tolerated after single administration in mice and rats, with LD50 values above 2000 and 5000 mg/kg for intraperitoneal and oral administration, respectively. In the oral subchronic toxicity studies, the histopathological examination performed after the 13-week treatment period confirmed the kidney as the target organ for toxicity. Increased presence of lipofuscin in the kidneys was observed in animals receiving 2000 or 450 mg/kg/d, and degeneration and/or dilatation of proximal renal tubules and chronic interstitial nephritis in males receiving these dosages. No histopathological findings were observed in the kidneys of animals receiving 100 mg/kg/d for 13 weeks. Other relevant findings were, presence of dark or cloudy urine with slightly lower pH in animals receiving dosages of 450 mg/kg/d and above, increased urinary protein concentration in animals receiving 2000 or 450 mg/kg/d, and increased plasma urea concentration in those receiving 2000 mg/kg/d. Moreover, increased plasma phospholipids and total cholesterol concentration, and increased liver and kidney weights were observed among treated animals. As a summary, the results have shown that irloxacin has a low acute toxicity in both mice and rats. For repeat oral administration in rats, 100 mg/kg can be considered as the non-toxic effect level after a treatment period of 13 weeks.     

The effect of polychlorinated biphenyls on liver gluconeogenic enzyme activities in rats during exposure to cold

Rats were fed diets containing either 0, 75, or 400 ppm Aroclor 1254. after 2 weeks on the diets, 4 animals per group were placed in the cold at 4° for an additional 2 weeks. Rats maintained at 4° gained less weight and had decreased adipose tissue weights as compared with animals at 25°. Ingestion of Aroclor 1254, a polychlorinated biphenyl (PCB), increased liver weights in the cold and at ambient temperature. Blood glucose was also significantly decreased in the cold-exposed rats fed 400 ppm PCB. At both temperatures, PCB decreased the specific activity (μmoles/g liver/min) of phosphoenol-pyruvate carboxykinase (PEPck) and fructose-1,6-diphosphatase (FDPase). Cold exposure significantly incresed the activity of PEPck and glucose-6-phosphatase (G-6-Pase) in rats fed PCB. When the activities were expressed as total μmoles/100 g body weight/min to correct for PCB-induced hepatomegaly, no significant differences were observed in the key gluconeogenic enzymes for PCB-fed rats at 25°. At 4°, FDPase and G-6-Pase activities were significantly increased with PCB feeding. Malic enzyme was significantly increased with PCB at both temperatures, regardless of the method of calculation. PCB ingestion had no effect on mitochondrial pyruvate metabolism. These studies indicate that ingestion of PCB (as Aroclor 1254) does not alter the response of the gluconeogenic enzymes to cold exposure.     

Oxidative stress induced in PCB 126-exposed northern leopard frogs, Rana pipiens

Northern leopard frogs Rana pipiens exposed to PCB 126 (3,3',4,4',5-pentachlorobiphenyl) were examined for hepatic oxidative stress. In a dose-response study, northern leopard frogs were injected intraperitoneally with either PCB 126 in corn oil (0.2, 0.7, 2.3, or 7.8 mg/kg body weight) or corn oil alone. In a time-course study, frogs received 7.8 mg/kg or corn oil alone, and were examined at 1, 2, 3, and 4 wk after dosing. Hepatic concentrations of reduced glutathione (GSH), thiobarbituric acid-reactive substances (TBARS), and total sulfhydryls (total SH), as well as activities of glutathione peroxidase (GSH-P), GSSG reductase (GSSG-R), glucose-6-phosphate dehydrogenase (G-6-PDH), and glutathione S-transferase (GSH-S-T) were measured. In the dose-response experiment, few effects were apparent 1 wk after dosing. In the time-course experiment, significant changes were observed in the 7.8-mg/kg group at 2 wk or more posttreatment. Hepatic concentrations of GSH and TBARS were higher than in corresponding controls at wk 3 and 4; the activities of GSSG-R and GSH-S-T were higher than in controls at wk 2 and 4; and the activity of G-6-PDH was increased at wk 2 and 4. These data collectively indicate that altered glutathione metabolism and oxidative stress occurred and were indicative of both toxicity and induction of protective mechanisms in frogs exposed to PCB. A similar delay in response was reported in fish and may relate to lower metabolic rate and physiological reactions in ectothermic vertebrates.     

Different starting times of α-tocopherol and γ-tocotrienol supplementation and tumor marker enzyme activities in-the rat chemically induced with cancer

• 1.1. α-Tocopherol (α-T) and γ-tocotrienol (γ-T) were supplemented continuously for 8 weeks in the diets of normal rats and rats chemically induced with cancer using diethylnitrosamine (DEN), 2-acetylaminofluorene (AAF) and partial hepatectomy. Hepatocarcinogenesis was followed by determining the plasma γ-glutamyl-transpeptidase (GGT) and alkaline phosphatase (ALP) activities as well as placental glutathione S-transferase (PGST) and GGT activities histochemically, at 4-week intervals.
• 2.2. Male Rattus norvegicus were supplemented α-T and γ-T at two different doses of 30 and 300 mg/kg diet. The supplementation was started at three different times: simultaneously with DEN administration; 4 weeks; and 8 weeks after DEN administration.
• 3.3. Elevation of plasma GGT activities and formation of PGST and GGT positive foci were attenuated significantly (P< 0.05) when α-T and γ-T were supplemented simultaneously with cancer induction. Supplementation begun 4 and 8 weeks after cancer induction did not affect plasma enzyme activities and formation of enzyme-positive foci.
• 4.4. α-T was more effective than γ-T, and a lower dose of 30 mg/kg was found to be more effective in reducing the severity of hepatocarcinogenesis.

     

Effects of development on acetoacetyl-CoA synthetase biosynthesis in rat liver.

In order to investigate the physiological role of acetoacetyl-CoA synthetase (acetoacetate-CoA ligase, EC 6.2.1.16), a cytosolic acetoacetate-activating enzyme, the effects of animal development on the activity and content of the enzyme were examined in rat liver. In male rats, the enzyme specific activity increased 21-fold at 4 weeks of age from that at 2 weeks of age, and then gradually decreased, while in female rats, it increased similarly to that of male rats, but further increased, reaching a maximum about 3-fold higher than that of male rats, at 6 weeks of age. The developmental patterns of the enzyme content correlated with that of the enzyme specific activity. These results indicate that changes in this enzyme activity and content during the developmental process might influence the rate of ketone body utilization for the formation of physiologically important lipidic substances in rat liver.     

蒿甲醚对小鼠体内日本血吸虫磷酸化酶,乳酸脱氢酶,三磷酸腺苷 …

目的：观察蒿甲醚（Ａｒｔ）对日本血吸早磷酸化酶（ＰＰ）、乳酶脱氢酶（ＬＤＨ）、６－磷酸工唿科（Ｇ－６－ＰＤＨ）和三磷酸腺苷酶（ＡＴＰａｓｅ）的影响。方法：感染３２－３８天的小鼠于灌服Ａｒｔ１００－３００ｍｇ．ｋｇ＾－１后２４－７２ｈ剖 杀，收集雌（♀）、雄虫（０１６５）、按ＮＡＤＨ和ＮＡＤＰＨ的形成和无机磷的释放量测定 上述４种酶。结果：感染小鼠用Ａｒｔ３００ｍｇ．ｋｇ＾－１治疗后２４－４８ｈ，♀     

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.