Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure of fed and fasted rats to CC1(4) vapor (114 ppm) for 6 h in a closed system increased serum enzyme activities (GOT, GPT, SDH) only in fasted animals. The in vivo metabolism of CC1(4), studied in the same system, was accelerated by fasting; the half-life of the elimination phase being reduced by approx. 33%. The enhanced susceptibility to CC1(4) induced by fasting seemed to be due to the accelerated bioactivation of CC1(4) to the toxic trichloromethyl free radical.
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PMID:Fasting accelerates the in vivo metabolism of carbon tetrachloride in rats. 708 97

In rats, i.v. administration of praseodymium, cerium and lanthanum (3 to 14 mg/kg) produced a dose-dependent increase in the serum activities of GOT, GPT and SDH. These dose-response curves of serum enzyme activities were shifted to the right by simultaneous treatment with silybin (75 mg/kg i.p.). Silybin also attenuated the increase of bromosulphthaleine retention and prevented the accumulation of liver triglycerides induced by praseodymium (7 mg/kg i.v.). Furthermore, silybin reduced the mortality rate of rats treated with high doses of the lanthanides. Rats treated with praseodymium (7 mg/kg i.v.) developed a pronounced hypoglycemia. On the 3rd day after praseodymium injection liver glycogen decreased to 4%, liver glutathione (GSH) to 82%, hepatic microsomal cytochrome P-450 content to 53%, aniline hydroxylase activity to 58% and aminophenazone demethylase activity to 40% of the control values. Silybin prevented praseodymium-induced hypoglycemia completely and the changes in the biochemical parameters of liver function partially but did not influence the decrease of liver GSH.
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PMID:The influence of silybin on the hepatotoxic and hypoglycemic effects of praseodymium and other lanthanides. 719 8

The hepatoprotective effect of carsil (generic name silymarin) on a model of liver intoxication with D-galactosamine in rats is studied. The changes in the activity of the serum enzymes GOT, GPT, MDH, SDH, ICDH, AP. AhE and the total protein as well as the UDP-sugars content in the liver is investigated. Histochemical and electronmicroscopical investigations of the liver are carried out simultaneously. It is obvious that carsil prevents to a considerable degree the increase of the serum enzymes activity caused by a D-galactosamine injury, enhances the metabolic conversion of the UDP-hexosamine into UDP-acetylhexosamine in the liver and hastens the normalizing of the UDP-glucuronic acid content in the liver of rats. The biochemical and morphological changes under the influence of carsil and the possible biochemical mechanism of the drug action is discussed.
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PMID:Hepatoprotective effect of silymarin (carsil) on liver of D-galactosamine treated rats. Biochemical and morphological investigations. 723 Sep 79

Liver and muscle amino acid enzyme activities and plasma proteins, urea, amino acids, glucose, lactate, 3-hydroxybutyrate and acetoacetate concentrations were studied in growing rats undergoing adaptation to high-fat, high-energy diet and glucose gavage. Liver and muscle were used for the estimation of alanine transaminase (GPT, EC 2.6.1.1.), adenylate deaminase (AMD, EC 3.5.4.6.), glutamine synthetase (GST, EC 6.3.1.2) and serine dehydratase (SDH, EC 4.2.1.13) activities, the latter only in liver samples. The most important modifications produced in muscle enzyme activities by glucose gavage were observed in rats fed a cafeteria diet. Glucose gavage affects liver enzyme activities in the same sense than cafeteria diet. Energy plasma components were affected in opposite way by glucose gavage according to diet administered.
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PMID:Changes induced in amino acid-enzymes of developing rats by a high-energy diet and glucose gavage. 768 82

The carcinogenic water disinfection byproduct, bromodichloromethane (BDCM), produces renal and hepatic toxicity in rodents in acute and subchronic studies. In the present investigation, female rats and mice (n = 6) were dosed daily for 5 consecutive days with BDCM (dissolved in an aqueous, 10% Emulphor solution) by gavage. Rats received 75, 150 and 300 mg BDCM/kg body weight/day and mice received 75 and 150 mg BDCM/kg body weight/day. Two rats in the 300 mg/kg/day treatment group died on day 5. On day 6, the animals were sacrificed and serum samples were taken for analysis of indicators of hepatic and renal toxicity. Livers and kidneys were excised and samples taken for histopathological evaluation. Portions of the livers were also utilized to produce microsomes for analysis of cytochrome P450 enzyme activities and total P450 content. Total hepatic cytochrome P450 was decreased in rats dosed with 150 and 300 mg BDCM/kg body weight/day, but was not significantly affected in BDCM-treated mice. Serum lactate (LDH) and sorbitol (SDH) dehydrogenase, aspartate aminotransferase (AST), creatinine and blood urea nitrogen were increased above those of controls in rats dosed with 300 mg BDCM/kg/day. These data suggested that hepatic and renal damage had occurred in this treatment group. This was confirmed by histopathological analyses which revealed that lesions occurred in both hepatic and renal tissues from rats dosed with 150 and 300 mg BDCM/kg/day. The hepatic lesions were centrilobular and primarily consisted of vacuolar degeneration. The hepatotoxicity indicators alanine aminotransferase (ALT) and SDH were increased in mice dosed with 150 mg BDCM/kg/day. However, no histopathological lesions were observed in these animals. This study shows that BDCM is both hepatotoxic and nephrotoxic to female rats after repeated dosing, but is only weakly hepatotoxic to female mice at the administered doses. Also, reduced activities of hepatic cytochrome P450 were observed in rats, but not mice. These species differences in toxicity and xenobiotic metabolizing enzyme inhibition caused by BDCM suggest that an understanding of the mechanism of toxicity of this compound will be critical when extrapolating rodent toxicity data to humans for this environmental pollutant.
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PMID:Toxicity of bromodichloromethane in female rats and mice after repeated oral dosing. 780 27

Simultaneous administration of trichloroethylene (TCE), at an oral dose of 0.5 ml/kg, resulted in a marked potentiation of liver injury caused by an oral dose of carbon tetrachloride (CCl4, 0.05 ml/kg). Hepatic glutathione levels were depressed at 24 hr only in the rats given TCE and CCl4. Using serum enzyme (ALT and SDH) as indicators of hepatotoxicity, potentiation of CCl4-injury was most apparent at 24 hr. Upon histological examination of H&E stained liver sections, the differences between livers obtained from TCE and CCl4-treated rats versus CCl4-treated rats were most apparent at later time points (48 and 72 hr). At 48 hr after CCl4, livers showed a distinctive and uniform pattern of injury with regeneration features predominating over necrosis. At this time, livers from TCE and CCl4-treated rats were characterized by extensive zone 3 coagulative necrosis. Inflammatory infiltrations were less prominent. At 72 hr, morphological features of livers from TCE and CCl4 rats were similar to those from rats given CCl4 alone at 48 hr. From the results obtained, it appears that the regenerative activity of the liver may be delayed in rats simultaneously administered TCE and CCl4 as compared to rats administered only CCl4.
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PMID:Time course of hepatic injury and recovery following coadministration of carbon tetrachloride and trichloroethylene in Fischer-344 rats. 824 22

Published reports on the alcohol potentiation of CCl4 toxicity indicate that in spite of enhanced hepatotoxicity there is no increase in lethality. The objective of this study was to investigate the mechanism involved in animal survival despite significantly enhanced liver injury. Male Sprague-Dawley rats (175-225 g) were treated with isopropanol (ISOP, 2.5 ml/kg, 25% aqueous solution, po) 24 hr prior to CCl4 (1 ml/kg, ip) administration. Plasma enzymes (ALT and SDH), hepatic glycogen levels, and [3H]thymidine (3H-T) incorporation into hepatonuclear DNA were measured during a time course (0-96 hr) after CCl4 administration. Liver sections were examined for histopathology and cell cycle progression by proliferating cell nuclear antigen (PCNA) immunohistochemistry. Maximum injury was observed at 36 hr in both the groups as indicated by elevated plasma enzyme levels and by histopathology. The extent of injury in the ISOP + CCl4 group was higher than that in the H2O + CCl4 group. Plasma enzyme activity returned to control levels by 60 hr, indicating recovery from injury in both groups. Maximum 3H-T incorporation occurred at 48 hr in both groups (ISOP + CCl4; vehicle + CCl4), indicating maximum stimulation of S-phase synthesis. PCNA studies revealed a corresponding stimulation of cell cycle progression. The wave of S-phase synthesis and cell cycle progression returned to control levels in the H2O + CCl4 group by 60 hr but continued up to 72 hr in the ISOP + CCl4 group. These findings support the hypothesis that in response to increased infliction of CCl4 injury by isopropanol, augmented stimulation of cell division and tissue repair restrain the progression of injury and restore hepatic structure and function, thereby allowing the rats to survive. Further, antimitotic intervention with colchicine (1 mg/kg, ip) led to decreased S-phase synthesis, followed by 60% lethality in the isopropanol-pretreated group in contrast to 40% lethality in the group receiving CCl4 alone (H2O + CCl4). These findings suggest that greater stimulation of tissue repair restrains the progression of ISOP-enhanced infliction of CCl4 liver injury and accounts for recovery from enhanced liver injury and animal survival. The findings are consistent with a two-stage model of toxicity wherein liver injury is linked by progression or regression of injury, which is governed by the extent of tissue repair to the final outcome.
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PMID:Stimulated tissue repair prevents lethality in isopropanol-induced potentiation of carbon tetrachloride hepatotoxicity. 888 39

1. The roles of cytochrome P450 monooxygenases (P450) and glutathione (GSH) in styrene hepatotoxicity were investigated in mice by pretreating with either phenobarbital (PB; P450 inducer), SKF 525A (P450 inhibitor), N-acetylcysteine (NAC; GSH precursor), or saline (vehicle control) prior to a 6-h exposure to either 500 ppm styrene on air. 2. Styrene caused hepatocellular degeneration or necrosis in all groups; these changes were more extensive and severe in mice pretreated with PB. Styrene significantly increased relative liver weights and serum ALT and SDH levels only in mice pretreated with PB. NAC did not prevent GSH depletion or hepatotoxicity. 3. In the fat of SKF 525A-pretreated mice a slight but statistically significant increase in styrene levels was observed, suggesting that metabolism was decreased; the SO/styrene ratio in the fat of PB-pretreated mice showed a slight, but statistically significant, increase indicating a slight increase in styrene metabolism. Neither SKF 525A nor PB caused changes in microsomal enzyme activity in vitro. 4. These results suggest that styrene may be activated by a pathway not totally dependent upon P450 enzyme activity, or more likely that PB and SKF 525A are not specific for the P450 enzymes involved in activation and detoxification of styrene.
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PMID:Effects of various pretreatments on the hepatotoxicity of inhaled styrene in the B6C3F1 mouse. 914 79

Although, hepatotoxic injury of 1,2-dichlorobenzene (o-DCB) is greater in Fischer 344 (F344) as compared to Sprague-Dawley (S-D) rats, this interstrain difference does not transcend into any difference in lethal effects of o-DCB. Interstrain difference in compensatory tissue repair has been suggested as the underlying mechanism for the lack of strain differences in lethality (S.G. Kulkarni, H. Duong, R. Gomila, and H.M. Mehendale, Strain differences in tissue repair response to 1,2-dichlorobenzene. Archives of Toxicology 1996; 70: 714-723). If higher tissue repair in F344 rats compensates for more severe liver injury, then antimitotic intervention after infliction of o-DCB-induced liver injury should lead to lethality in F344 rats. Colchicine (CLC, 1 mg/kg) functions as an effective antimitotic agent and does not cause any side effects apart from suppressing cellular proliferation. Two groups of male F344 rats (160-190 g) received a single dose of 0.6 ml o-DCB/kg: 30 h later one group of rats received CLC (1 mg/kg; i.p.) and the other received distilled water (1 ml/kg; i.p.). Liver injury was assessed by measuring plasma ALT and SDH activity, liver histopathology, and liver regeneration was estimated by [3H]thymidine incorporation into hepatonuclear DNA and proliferating cell nuclear antigen (PCNA) assay in both groups. Similar liver injury was noted in both the o-DCB + vehicle and o-DCB + CLC treated F344 rats at 36 h indicating that CLC does not interfere with the uptake, bioactivation and causation of injury by o-DCB. S-phase synthesis which occurred at 36 h in the o-DCB + vehicle group was blocked in the o-DCB + CLC group. CLC administration 6 h prior to S-phase stimulation selectively abolished S-phase stimulation at 36 h, and led to 50% lethality. Since the effect of CLC antimitosis was transient, S-phase synthesis occurring at 48 h was not blocked and was sustained up to 72 h thereby allowing the other 50% of rats to overcome liver injury induced by o-DCB and survive the lethal outcome. These findings suggest that a significantly higher rate of compensatory tissue repair in F344 rats enables them to overcome more severe liver injury inflicted by o-DCB.
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PMID:Antimitotic intervention with colchicine alters the outcome of o-DCB-induced hepatotoxicity in Fischer 344 rats. 918 94

Diet restriction is known to prevent a plethora of age-associated diseases including cancer. However, the effects of diet restriction on noncancer end points are not known. The objective of this study was to investigate whether diet restriction protects against hepatotoxicity of thioacetamide (TA), and if so, to investigate the underlying mechanism. Male Sprague-Dawley rats (250-275 g) were maintained on 65% of their ad libitum (AL) food consumption for a period of 3 weeks and then treated with a single low dose of 50 mg TA/kg i.p.. Plasma enzymes (ALT and SDH), hepatic glycogen levels, and 3H-thymidine incorporation into hepatocellular nuclear DNA were measured during a time course (0-120 h) after TA administration. Liver sections were examined for histopathology, and cell-cycle progression was assessed by proliferating cell nuclear antigen (PCNA) immunohistochemistry. In AL rats hepatic necrosis was evident at 12 h, peaked at 36 h, persisted up to 72 h, and was resolved by 96 h. In the diet-restricted (DR) group hepatic necrosis was observed at 12 h, peaked at 24 h, persisted till 72 h, and was resolved by 96 h. Maximal injury indicated by enzyme elevation occurred in DR rats and was approximately sixfold greater than that observed in the AL group. Histopathological examination of the liver sections revealed liver injury concordant with plasma enzyme elevations. There was a higher and sustained S-phase synthesis in the DR rats compared to AL group. S-phase stimulation was evident at 36 h, peaked at 48 h, and persisted until 96 h in the DR rats, whereas in the AL rats peak S-phase stimulation occurred at 36 h and subsided by 72 h. PCNA studies revealed a corresponding stimulation of cell-cycle progression indicating highly stimulated compensatory tissue repair. The 14-day lethality experiments (600 mg TA/kg i.p.) indicated 70% survival in the DR rats compared to 10% survival in the AL group. Although diet restriction increases hepatotoxic injury of TA, it protects from the lethal outcome by enhanced liver tissue repair. Comparison of liver injury and tissue repair employing an equitoxic dose (600 mg TA/kg in AL rats yields similar liver injury as observed with 50 mg TA/kg in DR rats) revealed that in spite of near equal injury up to 36 h, tissue repair response in DR rats is much higher. The compensatory tissue repair allows the DR rats to escape death in contrast to much lower compensation in AL rats leading to progression of liver injury culminating in death.
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PMID:Diet restriction enhances compensatory liver tissue repair and survival following administration of lethal dose of thioacetamide. 963 Apr 48


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