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:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protective action of aspartic acid on isolated and perfused rat liver was studied. In case of D-galactosamine intoxication the GOT, GPT and SDH activity and the lactate and pyruvate concentration in the perfusion medium were less augmented and the glycogen level in hepatic tissue was less diminished in animals treated with aspartic acid, as compared to controls. The histochemical applied (PAS reaction for glycogen, nucleic acids, NADH2-diaphorase, glucose-6-phosphatase and membrane-ATP-ase), also stated a protecting effect in the treated animals. The protective action of aspartate is hypothetically considered to be exerted by its capacity to reestablish the cellular deficit of pyridine nucleotides and thus to improve the synthesis of nucleic acids, glycoprotein and glycolipids or/and by its participation in various metabolic pathways.
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PMID:Protecting action of aspartate on the hepatic changes induced by D-galactosamine. 18 87

Coenzymes participate in many of the enzyme analyses performed in the clinical laboratory. Supplementation of assay systems with optimal levels of coenzymes has recently been recommended as part of efforts to achieve interlaboratory standardization of enzyme measurements. Aspartate aminotransferase and alanine aminotransferase require pyridoxal phosphate for expression of enzyme activity. The role of this coenzyme in enzymatic transamination and the effects of its supplementation on the clinical estimation of these two enzymes is reviewed. Other coenzymes discussed are flavins, coenzymes for glutathione reductase, glucose oxidase, cholesterol oxidase and diaphorase, as well as thiamine pyrophosphate, coenzyme for transketolase. Catalase and peroxidase are used as examples of hemoproteins utilized in clinical measurements. Two peptide coenzymes, colipase and glutathione, are also considered. Measurement of apoenzyme stimulation upon supplementation with specific coenzymes is discussed as a valuable technique for quantitative coenzyme measurements or assessment of vitamin nutritional status.
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PMID:Review: the role of coenzymes in clinical enzymology. 33 88

Short-term treatment of rats with hepatocarcinogens elicits a consistent pattern of phenotypic changes in hepatic drug metabolizing enzymes, the most striking of which is a marked increase in microsomal epoxide hydrolase (EH) activity. The antihistaminic drug methapyrilene induces a high incidence of hepatocellular carcinoma in F-344 rats. The studies reported here were designed to assess the effects of methapyrilene on hepatic EH activity, cytochrome P-450-dependent mixed-function oxidase activities, liver morphology, and liver-derived serum enzymes. Male F-344 rats were treated with three daily oral doses of methapyrilene-HCl, up to 300 mg/kg/day, and were sacrificed 48 hr after the last dose. Hepatic microsomal EH and cytosolic DT-diaphorase activities were increased in a dose-related fashion, to 420 and 230% of control, respectively. Cytochrome P-450 content and benzphetamine-N-demethylase and ethoxycoumarin-O-deethylase activities were concomitantly decreased to 35-50% of control. Serum gamma-glutamyl transpeptidase and alanine aminotransferase activities were elevated 22- to 27-fold, and serum bile acids to 36-fold by treatment with methapyrilene. Periportal lesions, characterized by inflammation, nuclear and nucleolar enlargement, bile duct hyperplasia, and hepatocellular necrosis, were observed following methapyrilene administration. The severity of the periportal lesion correlated with elevations in the serum chemistry parameters. The increases noted in microsomal EH activity supports the suggestion that this enzyme may be a useful biochemical marker for exposure to hepatocarcinogens.
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PMID:Effects of methapyrilene on rat hepatic xenobiotic metabolizing enzymes and liver morphology. 285 28

Inducers of Phase II enzymes, already consumed by humans as food additives, medicines or as constituents of vegetables, can prevent experimental carcinogenesis. Since protection is neither carcinogen- nor organ-specific, clinical trials are already underway to establish the efficacy of 'anticarcinogenic enzyme inducers' (i.e. oltipraz). However, efficient and cost-effective assays to establish the dose wherein a putative anticarcinogen can raise Phase II enzyme levels are lacking. We tested the proposal that serum Phase II enzyme activities would be dependent on relative tissue levels by measuring quinone reductase and glutathione S-transferase activities in sera of mice treated with dietary 2(3)-tert-butyl-4-hydroxyanisole (BHA) or dimethyl fumarate. Serum activities were significantly elevated in animals with increased tissue specific activities of these Phase II enzymes. Increasing concentrations of BHA in the diet from 0.05-0.5% increased hepatic specific activities of both QR and GST from two to six-fold, and increases in serum activities were well correlated to increases observed in the liver (r2 > or = 0.95). There was no evidence for an elevation of serum alanine aminotransferase levels. Thus, in the absence of serological evidence for hepatocellular damage, increased serum Phase II enzyme activities can be correlated to tissue levels. Our results suggest that similar assays tailored to human sera will not only be useful in the execution of chemoprevention trials, but also to assess the role that Phase II enzyme induction plays in the prevention of cancer by fruits and vegetables.
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PMID:Elevation of serum phase II enzymes by anticarcinogenic enzyme inducers: markers for a chemoprotected state? 826 10

Hepatic levels of GSH and Phase II detoxication enzymes were compared to biochemical and histological indices of hepatic damage in 4- to 76-week-old nontransgenic mice and their transgenic littermates that overexpress the hepatitis B virus large envelope protein. The mice were fed a low-sucrose AIN-76A diet ad libitum. Hepatic-specific activities of quinone reductase (QR) and glutathione S-transferase (GST) were increased 2- to 10-fold beginning at 12 weeks of age in transgenic mice and correlated with increases in serum alanine aminotransferase (ALT) (r = 0.84 and 0.59, respectively). Quantitative histological analysis demonstrated that apoptosis was the predominant feature in 4- to 12-week-old transgenic mice, whereas necrosis and inflammation predominated at later time points. Surprisingly, 3-fold elevations in ALT were observed beginning at 52 weeks of age in nontransgenic mice, and hepatic-specific activities of QR and GST were also modestly increased in elderly nontransgenic animals. In contrast to transgenic mice, apoptosis was not a prominent feature. The strongest histological correlates to ALT in 4- to 76-week-old nontransgenic mice were necrosis and inflammation (r > 0.96), which in turn may have been evoked by hepatic fat accumulation. Profiles of specific GST isoforms were quantitated chromatographically and identified by sequencing tryptic digests. The Ya1 subunit of alpha-class GST was markedly increased from undetectable levels in transgenic mice, while more modest increases were observed in nontransgenic mice more than 1 year old. Fivefold elevations of the Yb1 subunit, a constitutively expressed mu-class GST, were found in transgenic mice older than 4 weeks of age, while 2-fold increases were observed in nontransgenic animals that were more than 1 year old. These studies demonstrate that selected increases in Phase II detoxication enzymes are a stereotyped response to chronic hepatitis that is strikingly reminiscent of the treatment of mice with anticarcinogenic enzyme inducers.
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PMID:Elevations of hepatic quinone reductase, glutathione, and alpha- and mu-class glutathione S-transferase isoforms in mice with chronic hepatitis: a compensatory response to injury. 866 Jun 89

Novel thiazolidine prodrugs were prepared by the condensation of L-cysteine with aldose disaccharides. Using a disaccharide in prodrug construction allows for a terminal cyclic sugar moiety to be present on the prodrug, which may allow the delivery of the agent to specific receptors, such as the asialoglycoprotein receptor (ASGPR) of hepatocytes, that require specific structural motifs for recognition. Three L-cysteine prodrugs were synthesized with a pendant cyclic galactose moiety; two related glucose-bearing prodrugs were synthesized for comparison. The prodrugs were designed to release L-cysteine, which is then available to support glutathione (GSH) biosynthesis and provide cytoprotection against a variety of toxic insults. Protection studies in Swiss-Webster mice used acetaminophen (575 mg/kg), a well-documented hepatotoxin which depletes GSH at overdose. Three prodrugs performed exceptionally well against acetaminophen-induced hepatotoxicity, as measured by increased survival and improved histological profiles of liver tissue after 48 h. In further experimentation, two of the disaccharide-based prodrugs, prepared from alpha- and beta-lactose, were compared with the monosaccharide-based compound prepared from ribose. Co-administration of the selected prodrugs with a 400 mg/kg dose of acetaminophen to Swiss-Webster mice prevented the short-term depletion in hepatic GSH and also reduced hepatotoxicity as determined by histological damage and serum levels of alanine aminotransferase. A single dose of the prodrugs alone had no effect on hepatic drug metabolizing enzymes [glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase (QOR), UDP-glucuronosyltransferase (UGT), and cytochrome P450], but, concordant with the reduction of hepatotoxicity, the latentiated forms prevented the significant elevation in QOR activity and mRNA and GST mRNA elicited by acetaminophen itself. GST activity, UGT activity and mRNA, and cytochrome P450 concentration were all unaffected by acetaminophen or the prodrugs. These studies identified novel L-cysteine prodrugs with potentially useful hepatoprotective activity. However, no structure-activity relationships were obvious. In addition, the occurrence of targeted delivery to hepatocytes remains ambiguous.
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PMID:Differential chemoprotection against acetaminophen-induced hepatotoxicity by latentiated L-cysteines. 981 87

Recent metabolic studies have demonstrated the importance of reactive intermediates like quinones or semiquinone radicals in the covalent binding of halobenzenes to liver protein. The current studies were designed to examine if quinone intermediates are involved in the toxicity of hepatotoxic halobenzenes, bromobenzene (BB) and 1,2,4-trichlorobenzene (1,2,4-TCB). Two-electron reduction of the quinone intermediates by DT-diaphorase is considered to be a detoxication pathway since the resulting hydroquinone may be readily conjugated and excreted. Mice were pretreated with butylated hydroxyanisole (BHA; 0.5% in the diet, for 3 days), an inducer of DT-diaphorase, or dicoumarol (0.3 mmol/kg, p.o.), an inhibitor of this enzyme. The mice were then given BB (2.5 or 3.5 mmol/kg, i.p.) or 1,2,4-TCB (0.75 or 1.5 mmol/kg, i.p.). Dietary BHA markedly suppressed the hepatotoxicity caused by both BB and 1,2,4-TCB while dicoumarol significantly enhanced it, as judged by serum alanine aminotransferase activity. When mice were treated with BB at different times after the end of dietary BHA exposure, the degree of the protection against the hepatotoxicity appears to correlate to the extent of the induction of DT-diaphorase activity by BHA pretreatment. BHA pretreatment failed to protect against carbon tetrachloride-induced hepatotoxicity. These results seem to provide evidence for the involvement of the quinone metabolites in BB- and 1,2,4-TCB-induced hepatotoxicity and for the protective role of DT-diaphorase against the toxicity.
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PMID:Modulation of halobenzene-induced hepatotoxicity by DT-diaphorase modulators, butylated hydroxyanisole and dicoumarol: evidence for possible involvement of quinone metabolites in the toxicity of halobenzenes. 1009 53

Thymoquinone (TQ) is the major active component of the volatile oil of Nigella sativa seeds. The effects of TQ on carbon tetrachloride (CCl4)-induced hepatotoxicity was investigated in male Swiss albino mice. Carbon tetrachloride (20 microliters/Kg, i.p.) injected into mice, induced damage to liver cells and was followed by the increase in serum alanine aminotransferase (ALT) activity after 24 h. Oral administration of TQ in a single dose (100 mg/Kg) resulted in significant (p < 0.001) protection against the hepatotoxic effects of CCl4. TQ was tested as a substrate for mice hepatic DT-diaphorase in the presence of NADH. TQ appears to undergo reduction to dihydrothymoquinone (DHTQ). Reduction rates as a function of protein (liver homogenate) and substrate (TQ) concentrations are reported. An apparent K(m) of 0.1 mM and an apparent Vmax of 74 mumol/min/g liver were measured. TQ and DHTQ inhibited the in vitro non-enzymatic lipid peroxidation in liver homogenate (induced by Fe(3+)-ascorbate) in a dose dependent manner. In this in vitro model DHTQ was more potent in comparison with TQ and butylated hydroxytoluene (BHT). The IC50 for DHTQ, TQ and BHT were found to be 0.34, 0.87 and 0.58 microM respectively. The data suggest that the in vivo protective action of TQ against CCl4-induced hepatotoxicity may be mediated through the combined antioxidant properties of TQ and its metabolite DHTQ.
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PMID:Thymoquinone protects against carbon tetrachloride hepatotoxicity in mice via an antioxidant mechanism. 1009 55

Pretreating mice with schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, at a daily dose of 1 mmol/kg for 3 days protected against menadione-induced hepatic oxidative damage in mice, as evidenced by decreases in plasma alanine aminotransferase activity (78%) and hepatic malondialdehyde level (70%), when compared with the menadione intoxicated control. In order to define the biochemical mechanism involved in the hepatoprotection afforded by Sch B pretreatment, we examined the activity of DT-diaphorase (DTD) in hepatocytes isolated from Sch B pretreated rats. Hepatocytes isolated from Sch B pretreated (a daily dose of 1 mmol/kg for 3 days) rats showed a significant increase (25%) in DTD activity. The increase in DTD activity was associated with the enhanced rate of menadione elimination in the hepatocyte culture. The ensemble of results suggests that the ability of Sch B pretreatment to enhance hepatocellular DTD activity may at least in part be attributed to the protection against menadione hepatotoxicity.
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PMID:Schisandrin B protects against menadione-induced hepatotoxicity by enhancing DT-diaphorase activity. 1093 39

Our goal was to elucidate roles of Nrf2 in in vivo defense against pentachlorophenol (PCP), an environmental pollutant and hepatocarcinogen in mice. We examined oxidative stress and cell proliferation, along with other hepatotoxicological parameters, in the livers of nrf2-deficient (wild:+/+, heterozygous:+/-, homozygous:-/-) animals fed PCP in their diet at doses of 0, 150, 300, 600, or 1200 ppm for 4 weeks. For measurement of methoxyresorufin-O-demethylase (CYP 1A2), NAD(P):quinone oxidoreductase 1 (NQO1), and UDP-glucuronosyltransferase (UDP-GT), an additional study was performed with all but the 150-ppm dose. Significant elevation of 8-hydroxydeoxyguanosine (8-OH-dG) levels in the liver DNA was observed only in -/- mice treated with PCP at 1200 ppm. Levels of thiobarbituric-acid-reactive substances (TBARS) were also raised significantly compared to those of the relevant +/+ mice. Bromodeoxyuridine labeling indices (BrdU-LIs) of hepatocytes in -/- mice were significantly higher at all doses than those in the relevant +/+ mice. Relative liver weights were unchanged in mice lacking Nrf2, whereas liver weight in +/+ and +/- mice was increased. Significant elevations of serum ALP activity, but not ALT and AST activity, occurred at 600 ppm and above in -/- mice compared to the relevant +/+ mice. Histopathologically, centrilobular hepatocyte necrosis was severe in the -/- mice that received 600 ppm. Although CYP 1A2 activity was elevated in all treated mice, increases in NQO1 levels and UDP-GT activities did not occur only in -/- mice. These data suggest that Nrf2 plays a key role in prevention of PCP-induced oxidative stress and cell proliferation.
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PMID:A crucial role of Nrf2 in in vivo defense against oxidative damage by an environmental pollutant, pentachlorophenol. 1635 18


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