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)

This study assessed effects of exposure to p-xylene, a ubiquitous air pollutant, on mice infected with murine cytomegalovirus (MCMV), a mouse model for a common human virus. It was postulated that adverse health effects could occur as a result of (1) enhanced infection due to xylene-induced immune suppression, (2) increased p-xylene toxicity due to viral suppression of cytochrome P-450 (P-450), and/or (3) additive or synergistic effects on liver function due to tissue injury by both p-xylene and MCMV. Mice were exposed to filtered air, 600 or 1200 ppm p-xylene 6 h/d for 4 d and infected with a sublethal dose of MCMV after the first exposure. No deaths occurred among uninfected, p-xylene-exposed mice or infected, air-exposed mice; 34% and 0% mortality occurred respectively in infected mice exposed to 1200 and 600 ppm p-xylene. Virus titers in the liver and splenic natural killer cell activity were unaffected by exposure to 1200 ppm p-xylene. Small but significant increases in serum aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase activities, indicators of liver damage, were observed at 4 d postinfection. p-Xylene exposure had no effect on these serum enzyme activities in uninfected mice, but 1200 ppm potentiated this effect in infected mice. MCMV significantly suppressed and p-xylene significantly increased total P-450 levels in the liver, but there was no significant interaction between the two. Isozymes 1A1, 2B1/B2, and 2E1 were decreased to a similar degree, suggesting that the virus does not target specific isozymes. Enhanced mortality was not due to immune suppression. While p-xylene potentiated liver damage was caused by the virus, the magnitude of serum enzyme activities indicates that this damage was not a likely cause of death. The cause of deaths is unclear, results were consistent with the hypothesis that enhanced mortality was related to enhanced xylene toxicity due to suppression of P-450, although additive or synergistic damage to tissues other than liver cannot be ruled out.
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PMID:Enhanced mortality and liver damage in virus-infected mice exposed to p-xylene. 839 6

The expression of cytochromes P450 2E1, P450 2B and P450 1A was examined in rat hepatic tissue in response to YH439, an experimental hepatoprotective agent. P450 2E1 metabolic activities relatively specific for P450 2E1 were decreased up to 57% of control activities in the hepatic microsomes prepared from rats treated with YH439 for 3 days. Immunoblot analyses showed that P450 2E1 levels were decreased below the limit of detectability in hepatic microsomes prepared from YH439-treated rats. YH439 at doses from 25 to 100 mg/kg completely suppressed isoniazid-inducible P450 2E1 levels as monitored by both metabolic activities and immunoblot analysis. RNA hybridization analysis revealed that P450 2E1 mRNA levels failed to change after YH439 treatment. These results demonstrate the YH439 effectively suppresses P450 2E1 expression in the absence of transcriptional inactivation. YH439 failed to affect P450 2B1/2 expression, whereas this agent enhanced the hepatic P450 1A1/2 levels. The hepatoprotective effects of YH439 were also examined. Animals treated with CCl4 and ethanol for 9 weeks showed hepatic injury as demonstrated by 2.5- and 2-fold increases in serum alanine aminotransferase and alkaline phosphatase activities, respectively. Concomitant YH439 treatment resulted in a significant protective effect against the experimental hepatic injury. The toxicant-induced elevation in hepatic hydroxyproline level was completely blocked by YH439 treatment. These data indicate that YH439 suppresses the expression of P450 2E1 and protects the liver against chemical-induced hepatic injury and that the selective modulation of detoxifying enzymes by YH439 may contribute to the protection of liver from xenobiotic-induced intoxication.
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PMID:Suppression of rat hepatic cytochrome P450 2E1 expression by isopropyl 2-(1,3-dithioetane-2-ylidene)-2-[N-(4-methyl-thiazol-2-yl)carbamoyl] acetate (YH439), an experimental hepatoprotectant: protective role against hepatic injury. 893 29

3-Methylcholanthrene, an inducer of P448-type cytochromes (mostly 1A1 and 1A2), and phenobarbital, an inducer of P450-type cytochromes (mostly 2B1 and 2B2), are prototypical for the actions of many xenobiotics. They cause endocrine disruption by affecting, among others, steroid hormone levels. Rats were treated with single bolus doses of 3-methylcholanthrene or phenobarbital, and enzyme activities that are controlled by glucocorticoids were measured in liver and kidney. The activities of the cytosolic enzymes L-alanine aminotransferase, indoleamine 2,3-dioxygenase (L-tryptophan pyrrolase), phosphoenolpyruvate carboxykinase, L-serine dehydratase and L-tyrosine aminotransferase were affected in a similar fashion: an initial activity reduction followed by two overshoots of activity 1 and 2 days after dosing. 3-Hydroxy-3-methylglutaryl coenzyme A reductase, the microsomal key enzyme of sterol synthesis, responded with a temporary reduction of activity only and evidently lost its diurnal rhythm. The time course of these changes is most likely caused by a combination of sub-physiological levels of glucocorticoids plus changes of other regulatory hormones elicited by feed intake, postprandial state, etc. A possible role for a combined action of the arylhydrocarbon (Ah) and glucocorticoid receptors in the effects of 3-methylcholanthrene is also suggested.
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PMID:The enzyme inducers 3-methylcholanthrene and phenobarbital affect the activities of glucocorticoid hormone-regulated enzymes in rat liver and kidney. 962 May 44

Injection of acetaminophen (APAP) (350 mg/kg body weight) into C57BL/6 mice in which cytochrome P450 (CYP) 1A1/1A2 had been induced produced acute cataract and other ocular tissue damage. Treatment of APAP-injected mice with one of the major organosulfides in garlic oil, diallyl disulfide (DADS) (200 mg/kg body weight), prevented cataract development and prolonged survival time. N-acetyl L-cysteine (NAC) (500 mg/kg body weight), a prodrug that stimulates glutathione synthesis, also prolonged survival time but was effective only weakly to prevent cataract formation. A combination of DADS and NAC completely prevented cataractogenesis, and all of the treated animals survived APAP toxicity. Neither DADS nor NAC inhibited CYP 1A1/1A2 induction as determined by their effect on the induction of hepatic microsomal ethoxyresorufin O-dealkylase (ERD) activity. However, in the in vitro enzyme assay, DADS, but not NAC, was a potent inhibitor of ERD activity (IC50 = 3.5 mM). Treatment with DADS or NAC slowed but did not stop the decrease of hepatic glutathione (GSH) content. At 4 hours after APAP injection, hepatic GSH began to increase only when DADS and NAC were administered together. These results suggest that the protective effect of DADS is due to its inhibition of biotransformation of APAP to the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) by CYP 1A1/1A2 enzymes and that NAC provides protection by increasing cellular cysteine level and GSH synthesis, thus facilitating detoxification of NAPQI by glutathione conjugation. Assay of plasma glutamate-pyruvate transaminase activity, an indicator of liver necrosis, showed that treatment with DADS and NAC together effectively protected the liver. Therefore, the decrease of GSH as much as 30% of normal concentration, by itself, is not responsible for liver damage. The primary cause of hepatic necrosis is rapid accumulation of NAPQI.
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PMID:Prevention of acetaminophen-induced cataract by a combination of diallyl disulfide and N-acetylcysteine. 971 38

AIM:To assess the protective effect of diallyl disulfide (DADS) and its combined use with N-acetyl-cysteine (NAC) on acetaminophen (APAP) hepatotoxicity in C57BL/6N (B6) mice pretreated with beta-naphthoflavone (BNF).METHODS:B6 mice were divided into six groups and all compounds used were injected intraperitoneally. Except for control and APAP group (receiving APAP only), the other groups received an injection of APAP (350mg/kg) 48 hours after BNF (200mg/kg) and either of DADS (200mg/kg), or NAC (500mg/kg) or both DADS and NAC.DADS was given 2 hours before APAP and NAC was injected with APAP.The mean survival time was recorded and livers were examined histologically.Hepatic glutathione (GSH) levels and plasma ALT were also determined at different time points.To evaluate the effect of DADS or NAC on hepatic P450 induction by BNF,liver microsomes were prepared and 7-ethoxyresorufin O-dealkylase (ERD) activity was determined using spectrofluorometrical methods. In vitro effect of DADS or NAC on ERD activity was assayed by directly incubating microsomal suspension with DADS or NAC of different concentrations.RESULTS:APAP was not toxic to mice without BNF pretreatment, but caused severe liver necrosis and death of all BNF-treated mice in 4 hours. A sharp depletion of GSH (approximately 62% of its initial content at 2 hours and 67% at 4 hours) and a linear elevation of ALT levels (536.8 plus minus 29.5 Sigma units at 2 hours and 1302.5 plus minus74.9 at 4 hours) were observed.DADS and NAC given individually produced mild protection,resulting in prolonged survival,a slower decline of GSH level and a less steeper elevation of ALT level.All mice died eventually. Co-administration of DADS and NAC completely protected mice.GSH level in this group lowered by about 35% and 30% at 2 and 4 hours, and ALT was 126 plus minus 18 and 157.5 plus minus 36.6 Sigma units at 2 and 4 hours. ERD activity in BNF-treated mice was about 5 times that of the constitutive level determined in normal mice. Neither DADS nor NAC inhibited P450 1A1/1A2 induction as determined by their effect on the induction of ERD activity.In vitro assay indicates that DADS,but not NAC,was a potent inhibitor of ERD activity(IC(50) = 4.6&mgr;m).CONCLUSION:A combined use of both DADS and NAC produced full protection in BNF treated mice against APAP hepatotoxicity.The mechanism is that DADS inhibits P450 1A1/1A2 activity, but not induction, which substantially reduces production of NAPQI, while NAC enhances liver detoxifying capability via serving as a precursor of GSH and stimulating GSH synthesis.
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PMID:Effects of combined use of diallyl disulfide and Nacetyl-cysteine on acetaminophen hepatotoxicity in beta-naphthoflavone pretreated mice. 1181 51

Thiram is a dithiocarbamate compound widely used as an agricultural fungicide. This study examined the effect of cytochrome P450 (CYP) inducers on the metabolism and toxicity of thiram in rats. Rats were pretreated with 3-methyl cholathrene (3-MC), phenobarbital (PB), isoniazid (INH), or pregnenolone-16a-carbonitrile (PCN) as selective inducers of CYP 1A1, 2B1, 2E1 and 3A2, respectively. Thiram was administered ip to induced rats at 0.1 or 0.5 mmol/kg, and the animals were sacrificed 3 or 24 h later to assess P450 interaction and liver damage, respectively. No significant inhibition of 3-me-induced CYP1A1 was observed with either thiram dose at 3 or 24 h after treatment; similar results were noted for rats induced with PB or PCN. By contrast, when INH was the selective inducer of CYP2E1, there was significant inhibition by thiram 3 h and 24 h after treatment, suggesting that thiram was metabolized by the induced CYP2E1; there was a significant increase in ALT activity reflective of liver damage in the rats treated with thiram. The results suggest that CYP2EI induced by INH may be significantly involved in the metabolism of thiram, and the associated liver damage.
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PMID:Effect of cytochrome P450 inducers on the metabolism and toxicity of thiram in rats. 1245 34

The present study was done to determine the effect of trolox C, a hydrophilic analogue of vitamin E, on hepatic injury, especially the alteration in cytochrome P-450 (CYP)-dependent drug metabolism during ischemia and reperfusion (I/R). Rats were subjected to 60 min of hepatic ischemia and 5 h of reperfusion. Rats were treated intravenously with trolox C (2.5 mg/kg) or vehide (PBS, pH 7.4), 5 min before reperfusion. Serum alanine aminotransferase and lipid peroxidation levels were markedly increased after I/R. This increase was significantly suppressed by trolox C. Cytochrome P-450 content was decreased after I/R but was restored by trolox C. There were no significant differences in ethoxyresorufin O-dealkylase (CYP 1A1) and methoxyresorufin O-dealkylase (CYP 1A2) activities among any of the experimental groups. Pentoxyresorufin O-dealkylase (CYP 2B1) activity was decreased and aniline p-hydroxylase (CYP 2E1) activity was increased after I/R. Both these changes were prevented by trolox C. Our findings suggest that trolox C reduces hepatocellular damage as indicated by abnormalities in microsomal drug-metabolizing function during I/R, and that this protection is, in part, caused by decreased lipid peroxidation.
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PMID:Trolox C ameliorates hepatic drug metabolizing dysfunction after ischemia/reperfusion. 1251 Aug 51

The aim of this study was to investigate the effects of trauma on alterations in cytochrome P450 (CYP 450)-dependent drug metabolizing function and to determine the role of Kupffer cells in hepatocellular dysfunction. Rats underwent closed femur fracture (FFx) with associated soft-tissue injury under anesthesia, while control animals received only anesthesia. To deplete Kupffer cells in vivo, gadolinium chloride (GdCl3) was injected intravenously via the tail vein at 7.5 mg/kg body wt., 1 and 2 days prior to FFx surgery. At 72 h after FFx, serum alanine aminotransferase (ALT) activity was increased, and this increase was attenuated by GdCl3 pretreatment. Serum aspartate aminotransferase (AST) and lipid peroxidation levels were not changed by FFx. Hepatic microsomal CYP 450 content and aniline p-hydroxylase (CYP 2E1) activity were significantly decreased; decreases that were not prevented by GdCl3. The level of CYP 2B1 activity was decreased by Kupffer cell inactivation, but not by FFx. There were no significant differences in the activities of CYP 1A1, CYP 1A2 and NADPH-CYP 450 reductase among any of the experimental groups. Our findings suggest that FFx trauma causes mild alterations of hepatic CYP 450-dependent drug metabolism, and that Kupffer cells are not essential for the initiation of such injury.
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PMID:The roles of Kupffer cells in hepatocellular dysfunction after femur fracture trauma in rats. 1256 58

Crigler-Najjar syndrome is a recessively inherited disorder characterized by severe unconjugated hyperbilirubinemia caused by a deficiency of uridine diphospho-glucuronosyl transferase 1A1. Current therapy relies on phototherapy to prevent kernicterus, but liver transplantation presently is the only permanent cure. Gene therapy is a potential alternative, and recent work has shown that helper-dependent adenoviral (HD-Ad) vectors, devoid of all viral coding sequences, induce prolonged transgene expression and exhibit significantly less chronic toxicity than early-generation Ad vectors. We used a HD-Ad vector to achieve liver-restricted expression of human uridine diphospho-glucuronosyl transferase 1A1 in the Gunn rat, a model of the human disorder. Total plasma bilirubin levels were reduced from >5.0 mg/dl to <<1.4 mg/dl for >2 yr after a single i.v. administration of vector expressing the therapeutic transgene at a dose of 3 x 10(12) viral particles per kg. HPLC analysis of bile from treated rats showed the presence of bilirubin glucuronides at normal WT levels >2 yr after one injection of vector, and i.v. injection of bilirubins IIIalpha and XIIIalpha in the same animals revealed excess bilirubin-conjugating capacity. There was no significant elevation of liver enzymes (alanine aminotransferase) and only transient, moderate thrombocytopenia after injection of the vector. A clinically significant reduction in serum bilirubin was observed with a dose as low as 6 x 10(11) viral particles per kg. We conclude that complete, long-term correction of hyperbilirubinemia in the Gunn rat model of Crigler-Najjar syndrome can be achieved with one injection of HD-Ad vector and negligible chronic toxicity.
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PMID:Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector. 1575 92

Toona sinensis Roem (TS) leaf tea as a health food for the improvement of blood sugar and hypertension has been demonstrated. Thioacetamide (TAA), a hepatotoxin, causes the progression of liver fibrosis. In this study, we tested the effects of TS leaf on TAA-induced liver injury. TAA (200mg/kg Bwt/3 days, i.p.) treated rats were orally administrated with TS leaf extract (1g/kg Bwt/10 days) three times. After 30 days treatment, the morphological data showed that TS leaf extract given to TAA-treated rats had less liver fibrosis. The GOT/GPT, collagen 1 and collagen 3 mRNAs of livers in TAA-treated rats were elevated when compared to normal rats. The improvements of GOT/GPT, collagen 1 and collagen 3 mRNAs were shown in the TS leaf extract given to TAA-treated rats. TS leaf extract given to TAA-treated rats showed higher levels of cytochrome P450 (1A1, 2A and reductase) than those of TAA-treated rats. Compared to the TAA-treated group, TGFbeta1 mRNA (RT-PCR) was decreased with an increase of TGFbetaR1 protein (western blot) in the TS leaf extract given to TAA-treated rats. The decreased tendency of FGFR2 was found in the TS leaf extract given to TAA-treated rats. The result implies that TS leaf possesses beneficial effects on liver injury through increments of detoxification and the metabolic pathway.
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PMID:Toona sinensis Roem (Meliaceae) leaf extract alleviates liver fibrosis via reducing TGFbeta1 and collagen. 1762 4


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