Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.1 (aspartate aminotransferase)
 21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tightness of DNA-protein binding in the nuclei of mouse spleen T- and B-lymphocytes was assessed, using nucleoprotein celite chromatography, and changes in the number of T- and B-suppressors in the course of o-AAT-induced chemical hepatocarcinogenesis were studied. Attenuation of DNA-protein bonds in T-lymphocytes at the early stages (up to 3 months) was observed, and by the time of hepatoma formation (8 months) about 50% of T-lymphocyte DNA was loosely bound to proteins, which is a typical feature of quiescent cells. In B-lymphocytes attenuation of DNA-protein interaction was only observed by the 8th month of carcinogenesis. By the time of hepatoma formation the number of T-suppressors in mouse spleen increased 2.8-fold, while the number of B-suppressors in lymph nodes remained unchanged.
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PMID:[Change in the strength of DNA-protein binding in T- and B-lymphocytes of the spleen of C3HA mice during chemical hepatocarcinogenesis]. 387 31

Triplet repeats of the sequence purine, purine, and pyrimidine [RRY(i)] are frequent and often polymorphic in humans. Some RRY(i) are composed predominantly of a continuous repeat of one sequence [simple RRY(i)], but the majority are cryptic RRY(i) that are not obvious until the bases are classified into R or Y before the full extent of the repeat becomes apparent. RRY(i) can be divided into 18 classes based on predominant nucleotides. These classes are highly nonrandom in abundance and in location within genes. In humans, simple or cryptic RRY(i), in which AAT or AAC triplets predominate, are preferentially located 3' of Alu repeats. RRY(i) with a predominance of AGC or GGC show a dramatic enrichment in coding sequence, and GGC also shows a dramatic enrichment in 5' untranslated regions of genes. Characterization of RRY(i) present in coding regions identify 10 protein motifs (An, Dn, Hn, Pn, Qn, Tn, GnS0-3Gm, (G/S)n, (S/G/N)n, and (L/P)n). Six of the protein motifs appear predominantly in DNA-binding proteins/transcription factors. Alignment of homologous protein sequences from other mammals reveals that both simple and cryptic RRY(i) are a major source of deletions or insertions in the genes that contain them. Cryptic RRY(i) may be candidates for triplet repeat genetic diseases and, when mutated in somatic cells, may contribute to carcinogenesis.
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PMID:Nonrandom patterns of simple and cryptic triplet repeats in coding and noncoding sequences. 760 74

Rat hepatic aryl sulfotransferase IV (AST IV), which catalyses sulfuric acid esterification of N-hydroxy-2-acetylaminofluorene to its ultimate carcinogenic form, is differentially expressed during multistep 2-acetylaminofluorene (AAF) hepatocarcinogenesis. Two molecular mechanisms associated with this effect involve modulation of mRNA translational capacity at the early stages, and gene transcription at the late stages of the carcinogenic process. To characterize further the molecular mechanisms that may be involved in the transient regulation of the enzyme expression, an AST IV cDNA was used to assess the change in methylation profile and restriction fragment length polymorphism (RFLP) in the gene domain of genomic DNA derived from rats at different stages of carcinogenesis. The onset of hypomethylation of the AST IV gene domain and amplification of a 5.3-kb DNA sequence was found to correlate with the stage in AAF hepatocarcinogenesis, where rats begin to exhibit irreversible loss in hepatic enzyme expression and the liver becomes committed to hepatoma formation. This represents the first observation of both altered methylation status of AST IV gene domain and amplification of a DNA sequence whose expression may play a role in the genesis and/or progression of neoplastic transformation of initiated cells during AAF hepatocarcinogenesis.
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PMID:Hypomethylation of the rat aryl sulfotransferase IV gene and amplification of a DNA sequence during multistage 2-acetylaminofluorene hepatocarcinogenesis. 791 17

Numerous studies have indicated that two classes of cytosolic STs are involved in the bioactivation of procarcinogens and drugs to reactive electrophiles, especially in rodent tissues. These two classes of STs are the hydroxysteroid STs, which are involved in the conjugation of hydroxymethyl PAHs, and the phenol STs involved in the sulfation of alkenylbenzenes and N-hydroxyarylamines. Purification studies of rat liver STs have clearly indicated that specific isoforms of hydroxysteroid and phenol STs are capable of sulfating procarcinogens in vitro. Rat liver STa and BAST I are structurally similar hydroxysteroid STs, which have been shown to sulfate and bioactive HMBA. Molecular cloning studies of the rat hydroxysteroid STs indicate that these enzymes are probably part of a family of closely related genes. The single human hydroxysteroid ST that has been characterized is very similar to the rat enzymes, but its role in the bioactivation of hydroxymethyl PAHs has not been established. Phenol STs have been demonstrated to have an important role in the bioactivation of alkenylbenzenes and N-hydroxyarylamines. Purification of rat phenol STs has identified several different forms, but only some appear to be involved in bioactivation of procarcinogens. Four isoforms (HAST I and II, AST III and IV) are apparently responsible for the majority of N-hydroxyarylamine sulfation. The relationship between these enzymes has not been established but they may represent similar enzymes. Different isoforms of rat phenol ST are also involved in the bioactivation of procarcinogens and drugs. However, the role of these phenol STs, PST-1, Mx-ST, and paracetamol ST, in carcinogenesis requires further study. In human tissues, only two phenol STs, P-PST and M-PST, have been identified. The role of these enzymes or unidentified STs in the sulfation of N-hydroxyarylamine procarcinogens has not yet been established. Initial reports of the molecular cloning and expression of the rat and human phenol ST genes will provide a valuable mechanism for the characterization of roles of the individual enzymes in bioactivation.
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PMID:Biochemistry of cytosolic sulfotransferases involved in bioactivation. 806 57

A recent study from our laboratory demonstrated that cyclosporine (CsA), a prototype immunosuppressant, enhanced the growth of carcinogen-induced enzyme altered foci in rat liver, suggesting that CsA may stimulate development of hepatocellular carcinomas. In the present study, we examined (i) whether CsA accelerates development of hepatocellular carcinomas in experimental animals, (ii) whether CsA stimulates the proliferation of resting hepatocyte in vivo and (iii) whether CsA modulates the production of growth factors implicated in liver cell growth, hepatocyte growth factor (HGF), transforming growth factor alpha (TGF alpha) and transforming growth factor beta 1 (TGF beta 1). Foci of hepatocytes, positive for glutathione S-transferase placental form were induced in male F344 rats by a single dose of diethylnitrosamine followed by 7 weeks promotion by a choline-deficient diet. The animals were then divided in two groups, and subsequent development of hepatocellular carcinomas was compared in rats fed a basal diet or a basal diet containing 0.015% CsA. Development of hepatocellular carcinoma was accelerated in the rats maintained on a CsA diet. Feeding a CsA diet as the sole treatment, for 2, 4 and 10 weeks induced significant increases in liver weight, and resulted also in an enhanced incorporation by hepatocytes of 5-bromo-2-deoxy-uridine. Serum levels of glutamate-oxaloacetate transferase, glutamate-pyruvate transferase and lactic dehydrogenase were not altered by feeding a CsA diet. Northern Blot analyses of the expression of HGF, TGF alpha and TGF beta 1 mRNAs in the liver showed similar patterns of expression between rats fed a basal diet and a CsA diet. The levels of HGF mRNA were not altered in the lungs and kidneys of rats fed a CsA diet. These results indicate that CsA stimulates rat liver cell proliferation in vivo without inducing liver cell necrosis, and that this effect may contribute to accelerated development of hepatocellular carcinomas in rats fed a CsA diet. As previously observed with BR 931, a hypolipidemic peroxisome proliferator, stimulation of liver cell growth by CsA did not entail changes in the production of HGF, TGF alpha or TGF beta 1.
Carcinogenesis 1993 Aug
PMID:Cyclosporine stimulates hepatocyte proliferation and accelerates development of hepatocellular carcinomas in rats. 835 42

Several biochemical events accompany and mediate the development of chronic liver disease and its evolution into cancer. Low plasma zinc and high copper levels have been observed in various liver diseases, such as liver cirrhosis and viral hepatitis, while increased oestradiol levels have been documented in chronic liver damage and hepatocellular carcinoma. We administered CCL4 intragastrically to 10 female Sprague Dawley rats for 30 weeks. All animals developed cirrhosis and four also developed hepatocellular carcinoma. Plasma levels of zinc, copper and oestradiol were significantly higher in the latter group than in animals with simple cirrhosis. Progesterone, AST and bilirubin showed a trend toward significant differences whereas testosterone and ALP levels were unchanged. These findings add to the evidence that sex hormones and trace elements are involved in the process of the development of chronic liver damage and carcinogenesis.
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PMID:Sex hormones and trace elements in rat CCL4-induced cirrhosis and hepatocellular carcinoma. 835 89

Down regulation of aryl sulfotransferase IV (AST IV) in promotion/progression of liver carcinogenesis by N-2-fluorenylacetamide (2-FAA) has been established. This study examined whether the C-9 oxidized metabolites of 2-FAA, which have recently been shown to promote diethylnitrosamine (DEN)-initiated liver carcinogenesis in male Sprague-Dawley rats, effect the above change. Hence, in DEN-initiated rats, the effects of promoting regimens of 9-OH-2-FAA or 9-oxo-2-FAA, 15 oral doses at 50 and 100 mumol/kg of body weight, were compared to those of 2-FAA at 50 mumol/kg of body weight and of the vehicle on the activity of N-hydroxy(OH)-2-FAA sulfotransferase (ST), an isozyme of AST IV and AST IV expression and distribution. Relative to the vehicle, treatment with the fluorenyl compounds led to decreased levels in hepatic N-OH-2-FAA ST activity and development of hepatic nodules and tumors which had still lower levels of the ST activity than the respective remnant livers. At approximately 8 months after treatment with the C-9-oxidized compounds at doses twice that of 2-FAA, the extents of decreases in the hepatic N-OH-2-FAA ST activity and cytosolic AST IV protein in tumors were comparable to those with 2-FAA. Immunocytochemical analysis showed close association of AST IV deficiency with neoplastic liver lesions. In comparison to N-OH-2-FAA, 9-OH-2-FAA had only low and 9-oxo-2-FAA lacked sulfate acceptor activity in the presence of male rat liver cytosol or AST IV. At 3.3-fold greater concentration than N-OH-2-FAA, 9-oxo-2-FAA inhibited (27%) the sulfate acceptor activity of N-OH-2-FAA in the presence of AST IV, which suggested interference by 9-oxo-2-FAA at the active site. Although the C-9-oxidized compounds do not appear to be substrates for N-OH-2-FAA ST, their ability to cause a decrease in N-OH-2-FAA ST activity and protein similar to that of 2-FAA supports their role in hepatocarcinogenesis. Whereas 9-OH-2-FAA had a 3.9-fold greater sulfate acceptor activity in the presence of female than male rat liver cytosol and inhibited dehydroepiandrosterone ST activity of female rat liver, N-OH-2-FAA and 9-oxo-2-FAA inhibited estrone ST activity of male rat liver, suggesting that the C-9-oxidized compounds as well as N-OH-2-FAA are substrates for STs other than AST IV.
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PMID:Aryl sulfotransferase IV deficiency in rat liver carcinogenesis initiated with diethylnitrosamine and promoted with N-2-fluorenylacetamide or its C-9-oxidized metabolites. 931 85

Isopropyl-2-(1,3-dithietane-2-ylidene)-2-[N-(4-methylthiazol -2-yl)carbamoyl]acetate (YH439) is a novel dithioylidene malonate derivative developed for the treatment of hepatic injury. The compound has been found to down-regulate the expression of hepatic cytochrome P-450 2E1 (CYP2E1) at the transcriptional level (8). Certain organosulfur compounds present in garlic elicit protective effects on chemically induced carcinogenesis and mutagenesis and their chemopreventive activities are associated in part with inhibition of CYP2E1. As part of a program to determine the likely chemopreventive potential of YH439, we initially examined its effects on hepatotoxicity induced by vinyl carbamate (VC), a proximate carcinogen that is preferentially bioactivated by CYP2E1. A single i.p. injection of VC (125 mg/kg body wt) to male Sprague-Dawley rats resulted in severe hepatic lesions as demonstrated by elevated levels of serum enzymes such as alanine aminotransferase and aspartate aminotransferase. Histopathological evaluation of liver sections from VC-treated animals revealed that the hepatic damage mainly consisted of centrilobular necrosis with sinusoidal congestion. Oral administration of YH439 (200 mg/kg body wt) to male Sprague-Dawley rats 2 days, 1 day and 4 h prior to VC completely prevented the hepatic damage caused by this carcinogen. In another experiment, rat hepatic microsome-mediated bacterial mutagenicity of VC was suppressed by YH439 in a dose-related manner. Furthermore, pretreatment of female CD-1 mice with YH439 by gastric intubation resulted in diminution of VC-induced skin carcinogenesis.
Carcinogenesis 1998 Apr
PMID:Inhibition of vinyl carbamate-induced hepatotoxicity, mutagenicity, and tumorigenicity by isopropyl-2-(1,3-dithietane-2-ylidene)-2-[N-(4-methylthiazol-2- yl)carbamoyl]acetate (YH439). 960 Mar 56

2-(Allylthio)pyrazine (2-AP), synthesized for its possible use as a hepatoprotective agent, has been found to selectively inhibit rat hepatic cytochrome P450 2E1 (Kim et al., Biochem. Pharmacol., 53, 261-269, 1997), while it enhances the activities of phase II detoxification enzymes such as glutathione S-transferase and epoxide hydrolase. As part of a program in evaluating the chemopreventive potential of 2-AP, we have determined its effects on hepatotoxicity, mutagenicity and tumorigenicity of vinyl carbamate (VC), a prototypic hepatocarcinogen preferentially activated by P450 2E1 to the ultimate carcinogenic metabolite vinyl carbamate epoxide (VCO), which undergoes detoxification by glutathione conjugation and oxirane hydrolysis. Administration of 2-AP (100 mg/kg body wt) to male Sprague-Dawley rats by gavage, 2 days, 1 day and 4 h prior to VC or VCO, markedly ameliorated the hepatotoxicity of these compounds as determined by decreased serum aspartate aminotransferase and alanine aminotransferase activities. Furthermore, 2-AP pre-treatment significantly suppressed the VC-induced hepatocarcinogenesis in infant male B6C3F1 mice. In a separate experiment, the multiplicities of skin tumors formed in female ICR mice treated with 5.8 micromol of VC or VCO were inhibited 58 and 70%, respectively, by pre-treatment with 2-AP by oral administration. The mutational spectrum of ras-oncogene in papillomas was not altered by 2-AP pre-treatment. 2-AP also inhibited the mutagenicity of VC in the Salmonella-microsome assay. Taken together, these findings suggest that 2-AP is a potential chemopreventive agent.
Carcinogenesis 1998 Jul
PMID:Chemopreventive effects of 2-(allylthio)pyrazine on hepatic lesion, mutagenesis and tumorigenesis induced by vinyl carbamate or vinyl carbamate epoxide. 968 87

Glycyrrhizin (GL) is widely used in Japan as a therapeutic agent for chronic active liver diseases. However, its action on hepatocarcinogenesis remains to be elucidated. To clarify its effect, mice treated with diethylnitrosamine (NDEA) with or without GL were analyzed. Five-week-old male BALB/c mice were divided into two groups, GL (n=50) and C (n=47). Mice in the GL group intramuscularly received 2 mg of GL 3 days a week, and mice in the C group received the same volume of saline in the same way. After 2 weeks, the mice were treated with an i.p. injection of 75 mg/kg body wt of NDEA weekly for 3 weeks and 100 mg/kg body wt of NDEA weekly for the following 3 weeks. Thirty additional mice that did not receive NDEA treatment were divided into two groups, GC (n=15) and SC (n=15). They received GL or saline, respectively. Mice in the 4 groups were killed every 5 weeks after the last injection of NDEA from 7 weeks to 32 weeks. Liver function tests such as AST and albumin were significantly improved in the GL group compared with the C group (P < 0.05, each). Although liver nodules appeared in the C group at 22 weeks, they were not observed until 32 weeks in the GL group. At 32 weeks, the mean number of liver tumors, composed of adenoma and hepatocellular carcinoma (HCC), in the GL group was 0.71, which was significantly decreased compared with 1.64 of the C group (P < 0.05). The mean number of HCC in the GL group was 0.29/liver, which was lower than 0.82/liver in the C group (P < 0.05). The incidence rate of HCC at 32 weeks was 64% in the C group and 21% in the GL group (P < 0.05, C versus GL group). Our results suggest that GL treatment inhibits the occurrence of HCC.
Carcinogenesis 1999 Jan
PMID:Inhibition of hepatocellular carcinoma by glycyrrhizin in diethylnitrosamine-treated mice. 993 50


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