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)

Rat liver N-hydroxy-2-acetylaminofluorene (N-OH-2AAF) sulfotransferase activity is mediated by aryl sulfotransferase IV (AST IV) and causes the bioactivation of N-OH-2AAF to a highly reactive sulfuric acid ester form putatively capable of inducing liver cancer. Dietary administration of 2-acetylaminofluorene (2AAF) to induce hepatocarcinogenesis in rats has been shown to cause a rapid loss in N-OH-2AAF sulfotransferase activity. A possible mechanism for the in vivo loss in sulfotransferase activity may be the PAPS-dependent, sulfotransferase-catalyzed, reaction product inactivation of the enzyme by covalent reaction with the N-OH-2AAF sulfuric acid ester. In vitro studies to evaluate this possibility utilized a highly purified form of AST IV and measured the extent of PAPS-dependent interaction between the enzyme and N-OH-2[9-14C]AAF. The results showed the presence of a adenosine-3'-phospho-5'-phosphosulfate (PAPS)-dependent 14C-labeling of AST IV. The labeling could be blocked if the sulfotransferase inhibitor pentachlorophenol was present. Analysis of 14C-labeled AST IV following alkaline digestion and chromatography of digestion products indicated that AST IV cysteine and methionine residues were primary sites of 2[9-14C]AAF adduction. Studies involving the pretreatment of AST IV with PAPS and N-OH-2AAF prior to the measurement of N-OH-2AAF sulfotransferase activity showed a close parallel between formation of the AST IV cysteine-2AAF adduct and loss of activity. Similar studies showed that enzyme inactivation and cysteine-2AAF adduct formation could be blocked when excessive amounts of a competing nucleophile, methionine, were present during the pretreatment step, suggesting that inactivation does not proceed by a mechanism-based process. Finally, experiments involving prior reaction of AST IV with the thiol-blocking agent, N-ethylmaleimide, before measurement of enzyme activity showed essentially full loss of sulfotransferase activity and suggested that formation of AST IV cysteine-2AAF adducts could be a mechanism for enzyme inactivation. These results indicate that the in vitro inactivation of AST IV by the reactive N-OH-2AAF sulfuric acid ester is accompanied by covalent binding to AST IV, possibly through the formation of cysteine-2AAF adducts, and suggests that this mechanism merits further consideration as a basis for the loss of N-OH-2AAF sulfotransferase activity in vivo.
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PMID:Reaction product inactivation of aryl sulfotransferase IV following electrophilic substitution by the sulfuric acid ester of N-hydroxy-2-acetylaminofluorene. 173 62

The usefulness of the serum aspartate aminotransferase (AST): serum alanine aminotransferase (ALT) ratio as a guide to the presence of alcoholism was evaluated in four groups of patients. In alcoholics with elevated transaminases the mean AST:ALT ratio was found to be 1.50 (95% confidence interval (CI): 1.49-1.51), in hepatitis B infection 0.51 (95% CI: 0.50-0.52), in liver cancer 1.25 (95% CI: 1.20-1.29), and in nonmalignant obstructive jaundice 0.59 (95% CI: 0.57-0.61). In alcoholics with normal transaminases the AST:ALT ratio was 1.64 (95% CI: 1.61-1.67). The combination of an AST:ALT ratio of greater than 1.00 with an erythrocyte mean cell volume (MCV) above 90.0 fL resulted in a sensitivity of 97.3% and a specificity of 88.9% for detecting alcoholism in these four groups of patients.
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PMID:A combination of raised serum AST:ALT ratio and erythrocyte mean cell volume level detects excessive alcohol consumption. 238 15

Rat liver cytosolic sulfotransferase activity forms the highly reactive sulfuric acid ester of N-hydroxy-2-acetylaminofluorene (N-OH-2AAF), an ultimate carcinogen in 2-acetylaminofluorene (2AAF) hepatocarcinogenesis. A previous report demonstrated that 2AAF-induced liver hyperplastic nodules displayed a persistent loss of cytosolic N-OH-2AAF sulfotransferase activity following a hepatocarcinogenesis-producing regimen of 2AAF administration. As an initial step in examining the mechanism responsible for lowering N-OH-2AAF sulfotransferase activity, a monospecific polyclonal antibody to aryl sulfotransferase IV (AST IV) was produced and used in the assessment of AST IV as a candidate enzyme for liver cytosolic N-OH-2AAF sulfotransferase activity. Studies comparing the levels of N-OH-2AAF sulfotransferase activity of highly purified AST IV and rat liver cytosols with corresponding immunochemical analysis of AST IV contents demonstrated that there was sufficient AST IV activity in liver cytosols to indicate that it was the primary enzyme catalyzing cytosolic N-OH-2AAF sulfation. A subsequent immunochemical survey of nine extrahepatic tissues showed no detectable AST IV content and indicated that AST IV expression may be tissue specific. An immunochemical comparison of AST IV levels in control liver cytosols (high in sulfotransferase activity) with cytosols from 2AAF-derived hyperplastic nodules (low in sulfotransferase activity) or liver tumors (no sulfotransferase activity) showed low or no detectable levels, respectively, of AST IV. In addition, an immunochemical analysis of four rat hepatoma cell lines showed they contained no detectable levels of AST IV. These results suggested a strong correlation existed between a decrease in AST IV expression and tumor development. When the liver cytosols of rats taken from early, intermediate, and late stages of 2AAF carcinogenesis were analyzed for the development of a persistent loss of N-OH-2AAF sulfotransferase activity, a parallel loss of cytosolic N-OH-2AAF sulfotransferase activity and AST IV content was observed in rats which had proceeded from a stage of low risk to high risk for liver cancer. These findings indicated that (a) AST IV, a liver-specific enzyme, was the principle enzyme comprising cytosolic N-OH-2AAF sulfotransferase activity and (b) the decrease in sulfotransferase activity in nodules and tumors resulted from a decrease in the level of AST IV expression. Furthermore, it is suggested that a persistent decrease in AST IV expression may reflect a role for AST IV as part of a resistance phenotype in which transforming liver cells are able to escape the cytotoxic effects of highly reactive 2AAF metabolites and progress to cancer.
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PMID:2-Acetylaminofluorene-mediated alteration in the level of liver arylsulfotransferase IV during rat hepatocarcinogenesis. 238 38

Between December 1973 and September 1987, 21 patients with primary liver cancer and 41 patients with metastatic liver cancer were treated with external irradiation, intra-arterial infusion chemotherapy and/or transarterial embolization (TAE) at the National Medical Center Hospital, the National South Kyushu Central Hospital and the National Kure Hospital. Of the patients with primary liver cancer, 13 cases were treated with intra-arterial infusion chemotherapy (30-40 mg adriamycin or 10 mg mitomycin C) and hepatic irradiation. Eight cases were treated by TAE and hepatic irradiation. In the Child A group, the survival period of the chemotherapy + hepatic irradiation cases (mean: 608 days) was longer than that of the TAE + hepatic irradiation cases (mean: 216 days). The median survival period of all the cases was 7.0 months (mean: 10.9 months). For 16 of the 21 patients (who had absorbed over 40 Gy), the median survival period was 11.9 months (mean: 11.7 months). For 5 of the 21 patients (who had absorbed below 40 Gy), the median survival period was 4.3 months (mean: 7.9 months). Of the patients with metastatic liver cancer, the median survival period was 7.2 months (mean: 8.0 months). For 22 of the 41 patients (who had absorbed over 40 Gy), the median survival was 7.9 months (mean: 12.6 months). For 19 of the 41 patients (who had absorbed below 40 Gy), the median survival period was 1.7 months (mean: 2.6 months). The pretreatment serum GOT (glutamate oxaloacetate transaminase) levels and the pretreatment Karnofsky performance status index were the factors governing the prognosis of the cases with metastatic liver cancer, while toxicity was generally mild.
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PMID:Hepatic irradiation in primary and metastatic liver cancer. 292 86

Hepatocarcinogenesis is deterministic in transgenic mice expressing in the liver gene construct Alb-DS4 that encodes autocrine growth factor IgEGF (D Stern et al. (1987), Science 235: 321-324), causing their death within 7.1 months. Hepatic expression of construct AAT-myc encoding murine c-myc causes liver cancer in 44% of the mice at 14.8 months. Cooperation of these genes was evident in CD2F1 transgenics bearing Alb-DS4 plus AAT-myc, in which accelerated hepatocellular carcinoma (HCC) formation caused death of all mice within 4.4 months. Alb-DS4 also cooperates with the Hcs locus, which in C3H/HeJ mice mediates high susceptibility to spontaneous hepatocarcinogenesis, causing accelerated formation of HCC to which mice succumbed at 5.1 months. Thus, genes that predispose to HCC formation cooperate in transgenic mice and their interaction is a key to understand mechanisms that cause liver cancer.
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PMID:Autocrine mitogen IgEGF cooperates with c-myc or with the Hcs locus during hepatocarcinogenesis in transgenic mice. 786 54

Plachitin formed of both poly-N-acetyl-D-glucosamine (chitin) and cis-diamminedichloroplatinum (CDDP), was used as an arterial chemoembolization therapy against unresectable liver cancer. One gram of Plachitin contained 300 mg of CDDP. The Plachitin particle was 50-100 microns in diameter. Plachitin particles (50-100 mg) were injected via hepatic artery once or twice every week, and the total amount of 300 mg was considered one course of this therapy. The size and number of tumors were measured by computer tomography (CT). Pharmacokinetics of this drug was also assessed by serum and urine platinum (Pt) concentration. Three patients underwent the chemoembolization therapy using plachitin particles. Case 1 had multiple hepatocellular carcinomas. The tumor regression rate was 39% after two courses of this therapy. Serum alpha-fetoprotein (AFP) level decreased from 1,182 ng/ml to 300 ng/ml. Case 2 suffered from bile duct cystadenocarcinoma. After three courses of the therapy, the tumor regression rate was 84.4%. Serum carbohydrate antigen 19-9 (CA19-9) decreased from 731 U/ml to 75 U/ml. Case 3 had synchronous multiple liver metastases from sigmoid colon cancer. The tumor regression rate was 77% after one course of the therapy. Carcinoembryonic antigen (CEA) and CA19-9 decreased from 406 ng/ml to 65 ng/ml and from 4,800 U/ml to 790 ng/ml, respectively. The response rate of the 3 cases was 66.7%. The peak levels of the serum Pt concentration of three patients were 0-0.4 microgram/g throughout the therapy, but peak urine Pt concentrations were observed during one course of the therapy of three patients ranging from 0.5 microgram/g to 3.2 micrograms/g, and decreased gradually for three weeks after the first course. Adverse effects of Plachitin particles for arterial chemoembolization were epigastralgia, nausea, fever, and elevation of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. These adverse effects were observed in all patients, but were transient. Catheter obstruction occurred in one patient (case 2). Cholecystitis, pancreatic pseudocyst, and duodenal ulcer were noticed in case 3. No renal hypofunction was observed. Plachitin might be a useful agent for arterial chemoembolization therapy for primary and secondary liver cancer.
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PMID:[Intraarterial chemoembolization therapy for unresectable liver cancer using plachitin particles]. 794 46

Aflatoxin B1, a metabolite of Aspergillus flavus is a potent hepatotoxic and hepatocarcinogenic mycotoxin. Lipid peroxidation and oxidative DNA damage are the principal manifestations of aflatoxin B1-induced toxicity which could be mitigated by antioxidants. Many plant constituents, e.g. flavonoids, lignans and spice principles (capsaicin, curcumin, eugenol, etc.) have been reported to prevent liver damage associated with lipid peroxidation. In this study we investigated ternatin, a tetramethoxyflavone isolated from Egletes viscosa, for possible protection against liver injury induced by aflatoxin B1 in rats. Seventy two hours after a single intraperitoneal dose of aflatoxin B1 (1 mg kg(-1)), the concentration of malondialdehyde, the product of lipid peroxidation in liver homogenates, and serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly elevated (P<0.001). Subcutaneous ternatin (25 mg kg(-1)) pretreatment greatly reduced aflatoxin B1-induced increases in the levels of serum enzymes (ALT from 5071+/-763 to 293+/-66 international units L(-1) and AST from 4241+/-471 to 449+/-108 international units L(-1)) and elevated malondialdehyde levels (from 11.37+/-1.27 to 0.79+/-0.22 nmol (mg wet tissue)(-1)) in a manner similar to oral vitamin E (300 mg kg(-1)), a standard antioxidant. Further, histological changes induced by aflatoxin B1 such as hepatocellular necrosis and bile-duct proliferation were markedly inhibited in animals pretreated with ternatin or vitamin E. These data provide evidence that ternatin inhibits lipid peroxidation and affords protection against liver damage induced by aflatoxin B1. Ternatin might, therefore, be a suitable candidate for the chemoprevention of aflatoxicosis associated liver cancer.
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PMID:Inhibition by the bioflavonoid ternatin of aflatoxin B1-induced lipid peroxidation in rat liver. 1021 9

N,N-Dimethylformamide (DMF) has excellent solvent properties and is used intensively in the production of synthetic leather and resins. It has caused hepatoxicity in human and animal studies. Hepatitis B virus (HBV) and hepatitis C virus infections are reported to be the major causes of chronic liver diseases (including liver cirrhosis and liver cancer) in Taiwan. This study examined the dose-response relationship of the observed abnormal liver function among the DMF-exposed workers and the interactions among DMF, other chemical exposures, HBV infection, and potential confounders on liver abnormalities. The average DMF exposure concentration was 11.6 ppm (median, 5.9 ppm; range, 0.1 to 86.6 ppm); 65 of 176 workers (36.9%) had high (> 10 ppm) DMF exposure, 37 (21%) had middle (> 5 ppm, < or = 10 ppm) exposure, and 74 (42%) had low (< or = 5 ppm) exposure. There were 24 of 65 abnormal liver function test results (LFTs) (36.9%) (elevations of either glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, or gamma-glutamyl transpeptidase) among the workers with high DMF exposure, 10 of 37 abnormal LFTs (27%) among workers with middle DMF exposure, and 11 of 74 abnormal LFTs (22%) among workers with low DMF exposure. Compared with the workers having low DMF exposure, the HBV, drinking, body mass index (BMI), sex, duration of employment, epichlorohydrin, and toluene exposure adjusted odds ratios (ORs) (and 95% confidence intervals [CIs]) for abnormal LFTs were 1.62 (0.61, 4.28) for workers with middle DMF exposure and 2.93 (1.27, 6.8) for those with high DMF exposure, and there was a significant dose response between DMF exposure and the prevalence of abnormal LFTs (P = 0.006). There were significant associations between abnormal LFTs and HBV carriers (adjusted OR: 3.11; 95% CI: 1.29, 7.5; P = 0.01) and between abnormal LFTs and increased BMI (adjusted OR: 2.2; 95% CI: 1.02, 4.72; P = 0.041). Ultrasonography showed significant associations between chronic liver diseases and HBV carrier status, increased BMI, and high cumulative (> 100 ppm-years) DMF exposure (respectively, adjusted OR: 9.58, 95% CI: 1.79, 51.4, P = 0.007; adjusted OR: 13.2, 95% CI: 1.32, 132, P = 0.025; and adjusted OR: 6.2, 95% CI: 1.14, 34.1, P = 0.032). Drinking and BMI were significantly associated with fatty liver (respectively, adjusted OR: 4.9, 95% CI: 1.39, 17.3, P = 0.012; and adjusted OR: 7.93, 95% CI: 1.6, 39.3, P = 0.01). In conclusion, this study demonstrated that (1) a significant dose-response relationship existed between liver function abnormalities and DMF exposure among workers in Taiwan, (2) HBV carrier status or increased BMI had synergistic effects with DMF in causing liver abnormalities (abnormal LFTs and clinical chronic liver diseases).
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PMID:Abnormal liver function associated with occupational exposure to dimethylformamide and hepatitis B virus. 1138 83

Although hepatitis C virus (HCV)-related cirrhosis has been suggested as a risk factor for intrahepatic cholangiocarcinoma (ICC), few sizeable studies have tested this hypothesis. We investigated ICC risk factors, with special reference to HCV infection. We conducted a hospital-based case-control study including 50 ICC patients and 205 other surgical patients without primary liver cancer. HCV seropositivity was detected in 36% of ICC patients and 3% of controls. By univariate analysis, the odds ratio (OR) for association of anti-HCV antibodies with development was 16.87 (95% confidence interval (CI), 5.69 to 50.00). History of blood transfusion or diabetes mellitus, elevated serum total bilirubin, elevated aspartate aminotransferase and alanine aminotransferase, decreased serum albumin and decreased platelet count were identified as other possible ICC risk factors. By multivariate analysis, anti-HCV antibodies (adjusted OR, 6.02; 95% CI, 1.51 to 24.1), elevated alanine aminotransferase, decreased serum albumin, and decreased platelet count were found to be independent risk factors for ICC development. As liver status worsened, the adjusted OR for ICC tended to increase. HCV infection is a likely etiology of ICC in Japan.
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PMID:Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma. 1524 96

Hepatitis C is a major public health problem. General screening is not advisable and should be limited to risk groups. The gold standard for the assessment of disease severity is liver biopsy. AST and ALT do not correlate with histology. Serum HCV RNA by qualitative assay and HCV genotype should be determined prior to therapy. Response to antiviral therapy should be assessed by testing AST, ALT and qualitative HCV RNA. Repeat liver biopsy is not necessary. The incidence of HCC related to HCV infection is rising. Early detection by a cost effective screening program is essential. In patients with liver cirrhosis caused by hepatitis C, alpha fetoprotein and liver sonography should be done every 6 months. Upper GI endoscopy is recommended every 1-4 years in cirrhotic patients. Over 350 000 000 people are infected with HBV worldwide, and chronic HBV infection is the leading cause of liver cancer and tenth leading cause of death. HBs Ag, HBeAg and HBV DNA positive patients should be monitored for 6 months before treatment. Patients treated with antiviral therapy should be tested for HBAg, HBeAg and HBV DNA at the end of treatment and every 6 months thereafter to assess virologic response. Monitoring of serum HBV DNA is done by PCR. Patients treated with lamivudine should be tested for YMDD mutation. Ultrasound and AFP monitoring are recommended for detection of HCC, but results are not always reliable. Approximately 40% -70% of HIV infected patients have coinfection with HCV, HBV and HDV. HIV/HCV coinfected patients have an increased risk of progressive liver disease and should be treated accordingly.
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PMID:[Monitoring patients with chronic hepatitis during and after therapy]. 1638 Dec 36


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