Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.1 (aspartate aminotransferase)
21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thioacetamide (TA) is bioactivated by CYP2E1 to TA sulfoxide (TASO), and to the highly reactive sulfdioxide (TASO(2)), which initiates hepatic necrosis by covalent binding. Previously, we have established that TA exhibits saturation toxicokinetics over a 12-fold dose range, which explains the lack of dose-response for bioactivation-based liver injury. In vivo and in vitro studies indicated that the second step (TASO-->TASO(2)) of TA bioactivation is less efficient than the first one (TA-->TASO). The objective of the present study was to specifically test the saturation of the second step of TA bioactivation by directly administering TASO, which obviates the contribution from first step, i.e. TA-->TASO. Male SD rats were injected with low (50mg/kg, ip), medium (100mg/kg) and high (LD(70), 200mg/kg) doses of TASO. Bioactivation-mediated liver injury that occurs in the initial time points (6 and 12h), estimated by plasma ALT, AST and liver histopathology over a time course, was not dose-proportional. Escalation of liver injury thereafter was dose dependent: low dose injury subsided; medium dose injury escalated upto 36h before declining; high dose injury escalated from 24h leading to 70% mortality. TASO was quantified in plasma by HPLC at various time points after administration of the three doses. With increasing dose (i.e., from 50 to 200mg/kg), area under the curve (AUC) and C(max) increased more than dose proportionately, indicating that TASO bioactivation exhibits saturable kinetics. Toxicokinetics and initiation of liver injury of TASO are similar to that of TA, although TASO-initiated injury occurs at lower doses. These findings indicate that bioactivation of TASO to its reactive metabolite is saturable in the rat as suggested by previous studies with TA.
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PMID:Toxicokinetics and toxicity of thioacetamide sulfoxide: a metabolite of thioacetamide. 1718 15

Dichloromethane (DCM) is metabolically converted to carbon monoxide mostly by CYP2E1 in liver, resulting in elevation of blood carboxyhemoglobin (COHb) levels. We investigated the effects of a subtoxic dose of acetaminophen (APAP) on the metabolic elimination of DCM and COHb elevation in adult female rats. APAP, at 500 mg/kg i.p., was not hepatotoxic as measured by a lack of change in serum aspartate aminotransferase, alanine aminotransferase, and sorbitol dehydrogenase activities. In rats pretreated with APAP at this dose, the COHb elevation resulting from administration of DCM (3 mmol/kg i.p.) was enhanced significantly. Also blood DCM levels were reduced, and its disappearance from blood appeared to be increased. Hepatic CYP2E1-mediated activities measured with chlorzoxazone, p-nitrophenol, and p-nitroanisole as substrates were all induced markedly in microsomes of rats treated with APAP. Aminopyrine N-demethylase activity was also increased slightly, but significantly. Western blot analysis showed that APAP treatment induced the expression of CYP2E1 and CYP3A proteins. Neither hepatic glutathione contents nor glutathione S-transferase activity was changed by the dose of APAP used. The results indicate that, contrary to the well known hepatotoxic effects of this drug at large doses, a subtoxic dose of APAP may induce CYP2E1, and to a lesser degree, CYP3A expression. This is the first report that APAP can increase cytochrome P450 (P450)-mediated hepatic metabolism and the resulting toxicity of a xenobiotic in the whole animal. The pharmacological/toxicological significance of induction of P450s by a subtoxic dose of APAP is discussed.
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PMID:Induction of hepatic CYP2E1 by a subtoxic dose of acetaminophen in rats: increase in dichloromethane metabolism and carboxyhemoglobin elevation. 1762 Mar 48

Although dietary restriction (DR) is common in modern society, research about hepatic metabolism and the hepatotoxicity induced by DR has been conducted less intensively than that induced by fasting. In the present study, we fed male Wistar rats at five levels of food intake for one day, including conventional feeding (60 kcal), three of DR (45, 30, and 15 kcal), and fasting (0 kcal), and observed the metabolic changes of hepatic cytochrome P450 2E1(CYP2E1) and the hepatotoxicity of chloroform (CHCl(3)) and carbon tetrachloride (CCl(4)). The CYP2E1 content was significantly increased in 15 kcal-food and fasting groups. The hepatic glutathione (GSH) content, which protects the liver from hepatotoxic agents, was depleted in 15 kcal-food and fasting groups. After the challenge by CHCl(3) and CCl(4), the activities of aspartate aminotransferase and alanine aminotransferase, marker enzymes for liver damage, were elevated remarkably at all food groups. Moreover, their activities increased significantly in DR groups, in comparison to the corresponding 60 kcal-food group. After the challenge, the hepatic GSH content was also depleted significantly in 15 kcal-food and fasting groups. CHCl(3) was cleared by hepatic metabolism about 8-10 times faster than that of CCl(4). Similarly, the areas under the blood concentration-time curve of CCl(4) was as much as twice that of the corresponding CHCl(3). In conclusion, when food was restricted to less than half of conventional amount, hepatic metabolism was affected and the hepatotoxicity induced by CCl(4) or CHCl(3) was augmented by, at least in part, CYP2E1 induction and GSH depletion.
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PMID:One-day dietary restriction changes hepatic metabolism and potentiates the hepatotoxicity of carbon tetrachloride and chloroform in rats. 1766 Jul 3

Puerarin, the main isoflavone glycoside found in the root of Pueraria lobata, has been used for various medicinal purposes in traditional Chinese medicine for thousands of years. The purpose of this study was to investigate the protective effects of puerarin against hepatotoxicity induced by carbon tetrachloride (CCl4) and the mechanism of its hepatoprotective effect. In mice, pretreatment with puerarin prior to the administration of CCl4 significantly prevented the increased serum enzymatic activity of alanine aspartate aminotransferase and hepatic malondialdehyde formation in a dose-dependent manner. In addition, pretreatment with puerarin significantly prevented both the depletion of reduced glutathione (GSH) content and the decrease in glutathione S-transferase (GST) activity in the liver of CCl4-intoxicated mice. Hepatic GSH levels and GST activity were increased by treatment with puerarin alone. CCl4-induced hepatotoxicity was also prevented, as indicated by liver histopathology. The effects of puerarin on cytochrome P450 (CYP) 2E1, the major isozyme involved in CCl4 bioactivation, were also investigated. Treatment of the mice with puerarin resulted in a significant decrease in the CYP2E1-dependent aniline hydroxylation in a dose-dependent manner. Consistent with these observations, the CYP2E1 protein levels were also lowered. Puerarin exhibited anti-oxidant effects on FeCl2-ascorbate induced lipid peroxidation in mouse liver homogenates, and on superoxide radical scavenging activity. These results suggest that the protective effects of puerarin against the CCl4-induced hepatotoxicity possibly involve mechanisms related to its ability to block CYP-mediated CCl4 bioactivation, induction of GST activity and free radical scavenging effects.
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PMID:Protective effects of puerarin on carbon tetrachloride-induced hepatotoxicity. 1803 10

To assess the effect of gadolinium (Gd) on the expression of several forms of cytochrome P450 (P450s) and antioxidant enzymes, we treated rats with gadolinium chloride (25 mg as Gd/kg body weight) 4 h after styrene (a multiple P450 inducer) treatment (600 mg/kg). Gd treatment significantly suppressed styrene-inducible cytochrome P4502B1 (CYP2B1), CYP2B2, CYP2E1, and CYP3A2 mRNA expressions to 48.6%, 69.8%, 61.1%, and 38.5%, accompanying with the reduction of proteins expression to 1.42%, 31.2%, 21.1% and 21.1%, respectively, compared with styrene alone treatment. Gd suppressed styrene-inducible CYP1A2 expression, but only at the protein level. On the other hand, styrene treatment caused a decrease in reduced form of glutathione (GSH), as well as increases in lipid peroxide and serum ALT and AST activities, suggesting the occurrence of hepatic damage probably due to styrene-induced oxidative stress in rat liver. Post-treatment of Gd attenuated this styrene-caused hepatic damage. Moreover, mRNA expressions of cellular antioxidant enzymes such as catalase, CuZn-superoxide dismutase (CuZnSOD) and glutathione peroxidase (GPX) were hardly changed by styrene and/or Gd treatment. In summary, Gd suppressed styrene-inducible expression of not only CYP2B1 but also several forms of P450 at both the mRNA and protein levels, along with attenuation of styrene-caused liver damage. These findings suggested that Gd is a chemo-preventive agent against hepatic damage caused by xenobiotics requiring biotransformation.
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PMID:Gadolinium chloride suppresses styrene-induced cytochrome P450s expression in rat liver. 1820 23

The purpose of this study was to investigate the protective effects of the saponins isolated from the root of Platycodi Radix (Changkil saponins: CKS) on carbon tetrachloride (CCl(4))-induced hepatotoxicities in mice. Pretreatment with CKS prior to the administration of CCl(4) significantly prevented the increase in serum alanine aminotransferase and aspartate aminotransferase activities and hepatic lipid peroxidation formation. In addition, CKS prevented CCl(4)-induced apoptosis and necrosis, as indicated by a liver histopathologic study and DNA laddering. To determine whether Fas/Fas ligand (FasL) pathway involved in CCl(4)-induced acute liver injury, Fas and FasL proteins and caspase-3, -8 activities were tested by western blotting and ELISA. CKS markedly decreased CCl(4)-induced Fas/FasL protein expression levels and in turn attenuated CCl(4)-induced caspase-3, -8 activities in mouse livers. Additionally, CKS protected the CCl(4)-induced depletion of hepatic glutathione levels. The effect of CKS on CYP2E1, the major isozyme involved in CCl(4) bioactivation, was investigated. Treatment with CKS resulted in a significant decrease in the CYP2E1-dependent hydroxylation of aniline. In addition, CKS exhibited antioxidant effects on FeCl(2)-ascorbate induced lipid peroxidation in liver homogenates, and on superoxide radical scavenging activity. These findings suggest that the protective effects of CKS against CCl(4)-induced acute liver injury possibly involve mechanisms related to its ability to block CYP2El-mediated CCl(4) bioactivation and its free radical scavenging effects, and that is also protects against Fas/FasL pathway mediated apoptosis.
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PMID:Protective effect of saponins derived from the roots of Platycodon grandiflorum against carbon tetrachloride induced hepatotoxicity in mice. 1829 69

Previous experiments showed that treatment of mice and rats with thioacetamide (TAA) induced liver cell damage, fibrosis and/or cirrhosis, associated with increased oxidative stress and activation of hepatic stellate cells. Some experiments suggest that CYP2E1 may be involved in the metabolic activation of TAA. However, there is no direct evidence on the role of CYP2E1 in TAA-mediated hepatotoxicity. To clarify this, TAA-induced hepatotoxicity was investigated using Cyp2e1-null mice. Male wild-type and Cyp2e1-null mice were treated with TAA (200 mg/kg of body weight, single, i.p.) at 6 weeks of age, and hepatotoxicity examined 24 and 48 h after TAA treatment. Relative liver weights of Cyp2e1-null mice were significantly different at 24 h compared to wild-type mice (p<0.01). Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) in Cyp2e1-null mice were significantly different at both time points compared to wild-type mice (p<0.01). Histopathological examination showed Cyp2e1-null mice represented no hepatototoxic lesions, in clear contrast to severe centriobular necrosis, inflammation and hemorrhage at both time points in wild-type mice. Marked lipid peroxidation was also only limited to wild-type mice (p<0.01). Similarly, TNF-alpha, IL-6 and glutathione peroxidase mRNA expression in Cyp2e1-null mice did not significantly differ from the control levels, contrasting with the marked alteration in wild-type mice (p<0.01). Western blot analysis further revealed no increase in iNOS expression in Cyp2e1-null mice. These results reveal that CYP2E1 mediates TAA-induced hepatotoxicity in wild-type mice as a result of increased oxidative stress.
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PMID:Role of CYP2E1 in thioacetamide-induced mouse hepatotoxicity. 1837 80

This study was designed to investigate the protective effects of the phenethyl ester of caffeic acid (CAPE) against carbon tetrachoride (CCl(4))-induced hepatotoxicities in mice. Pretreatment with CAPE prior to administration of CCl(4) significantly prevented the increases in serum alanine, aspartate aminotransferase and alkaline phosphatase activities, hepatic lipid peroxidation formation, and depletion of glutathione content. In addition, CAPE prevented CCl(4)-induced apoptosis and necrosis, as indicated by liver histopathology and DNA laddering studies. To determine whether the Fas/Fas ligand (FasL) pathway is involved in CCl(4)-induced acute liver injury, Fas and FasL proteins and caspase-3 and -8 activities were tested by western blotting and ELISA. CAPE markedly decreased CCl(4)-induced Fas/FasL protein expression levels and, in turn, attenuated CCl(4)-induced caspase-3 and -8 activities in mouse liver. Moreover, the effect of CAPE on CYP2E1, the major isozyme involved in CCl(4) bioactivation, was investigated. Treatment with CAPE significantly decreased the CYP2E1-dependent hydroxylation of aniline. In addition, CAPE attenuated the CCl(4)-mediated depletion of antioxidant enzyme (catalase, superoxide dismutase and glutathione-S-transferase) activities. These findings suggest that the protective effects of CAPE against CCl(4)-induced acute liver injury may involve its ability to block CYP2El-mediated CCl(4) bioactivation and to protect against Fas/FasL-mediated apoptosis.
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PMID:Protective effect of caffeic acid phenethyl ester against carbon tetrachloride-induced hepatotoxicity in mice. 1843 64

Cytochrome P450 (CYP) 2E1 was suggested to be the major enzyme involved in trichloroethylene (TRI) metabolism and TRI-induced hepatotoxicity, although the latter molecular mechanism is not fully understood. The involvement of CYP2E1 in TRI-induced hepatotoxicity and its underlying molecular mechanism were studied by comparing hepatotoxicity in cyp2e1+/+ and cyp2e1-/- mice. The mice were exposed by inhalation to 0 (control), 1000, or 2000 ppm of TRI for 8 h a day, for 7 days, and TRI-hepatotoxicity was assessed by measuring plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and histopathology. Urinary metabolites of trichloroethanol and trichloroacetic acid (TCA) were considerably greater in cyp2e1+/+ compared to cyp2e1-/- mice, suggesting that CYP2E1 is the major P450 involved in the formation of these metabolites. Consistent with elevated plasma ALT and AST activities, cyp2e1+/+ mice in the 2000 ppm group showed histopathological inflammation. TRI significantly upregulated PPARalpha, which might function to inhibit NFkappaB p50 and p65 signalling. In addition, TRI-induced NFkappaB p52 mRNA, and significantly positive correlation between NFkappaB p52 mRNA expression and plasma ALT activity levels were observed, suggesting the involvement of p52 in liver inflammation. Taken together, the current study directly demonstrates that CYP2E1 was the major P450 involved in the first step of the TRI metabolism, and the metabolites produced may have two opposing roles: one inducing hepatotoxicity and the other protecting against the toxicity. Intermediate metabolite(s) from TRI to chloral hydrate produced by CYP2E1-mediated oxidation may be involved in the former, and TCA in the latter.
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PMID:Molecular mechanism of trichloroethylene-induced hepatotoxicity mediated by CYP2E1. 1856 63

Synergistic therapeutic potential of ferritin (5mg/kg, i.p.) and propolis (honeybee hive product; 200mg/kg, p.o.) was analyzed to encounter the beryllium induced biochemical and ultra morphological alterations. Female albino rats were exposed to beryllium nitrate (1mg/kg, i.p.) daily for 28 days followed by treatment of above mentioned therapeutic agents either individually or in combination for five consecutive days. Exposure to beryllium increased its concentration in serum, liver and kidney and significantly altered the activities of CYP2E1 and CYP1A2 enzymes, microsomal lipid peroxidation and microsomal proteins. Activities of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyl transpeptidase, bilirubin, protein, creatinine and urea in serum as well as hemoglobin and blood glucose level; activity of acid phosphatase, alkaline phosphatase, adenosine triphosphatase, glucose-6-phosphatase and succinic dehydrogenase, total triglycerides, total cholesterol, total protein contents, glycogen contents, lipid peroxidation and glutathione level in liver and kidney were significantly altered after beryllium administration. Beryllium exposure severely altered ultramorphology of liver and kidney that proved its toxic consequences at cellular level. Ferritin in combination with propolis dramatically reversed the alterations of these variables towards control in a synergistic manner concluding its beneficial effects over monotherapy in attenuating beryllium induced systemic toxicity.
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PMID:Synergistic effects of ferritin and propolis in modulation of beryllium induced toxicogenic alterations. 1862 18


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