Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related environmental pollutants exert most of their adverse effects via the aryl hydrocarbon or dioxin receptor (AhR). While most potent agonists of the AhR are of synthetic origin, an increasing number of natural compounds is now recognized as receptor agonists. Our findings demonstrate that some tryptanthrin derivatives biosynthesized in incubations of Candida lipolytica with tryptophan and anthranilic acid or its derivatives activate the AhR measured as induction of cytochrome P4501A1 mRNA and protein in rat hepatocytes in primary culture. The specificity of the inducing effect of tryptanthrins was demonstrated in gel retardation experiments in Hepa-1 mouse hepatoma cells using an oliogonucleotide comprising the sequence of the dioxin-responsive element. Furthermore, unidentified AhR agonists were formed in incubations of rat feces with a minimal medium supplemented with tryptophan. It is suggested that the receptor may be part of a defense system protecting higher organisms from secondary tryptophan-derived metabolites formed by the microflora of the host or its environment.
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PMID:Tryptanthrins and other tryptophan-derived agonists of the dioxin receptor. 1072 Oct 82

The present investigation was undertaken to determine whether administration of O3-oxidized amino acids to mouse hepatoma cells, Hepa lclc7 (Hepa-1), in culture would effect Cyp1a1 gene expression. The results demonstrate that, of all the amino acids tested, only O3-oxidized tryptophan caused a significant induction of CYP1A1-dependent 7-ethoxyresorufin O-deethylase (EROD) activity compared to the controls (p < 0.01). CYP1A1 mRNA and protein were markedly induced in the O3-oxidized tryptophan administered group compared to the controls. Gel mobility shift assays using nuclear extracts of Hepa-1 cells revealed that oxidized products of tryptophan can induce both aryl hydrocarbon receptor (AhR) transformation and binding of the liganded AhR complex to its specific DNA recognition site, thereby initiating transcription of the Cyp1a1 gene with concomitant increase of CYP1A1 protein and EROD activity in Hepa-1 cells.
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PMID:Induction of cytochrome P4501A1 by ozone-oxidized tryptophan in Hepa lclc7 cells. 1072 Oct 83

Previous studies from this laboratory have shown that L-tryptophan, after oxidation by either ultraviolet (UV) irradiation or ozone, causes induction of cytochrome P450 (CYP)1A1 mRNA, protein, and the corresponding 7-ethoxyresorufin O-deethylase (EROD) activity in wild type mouse hepatoma cells, Hepa lclc7 (Hepa-1), through the aryl hydrocarbon receptor (AhR). In the present study, we have examined the effect of temporary inhibition of protein synthesis by cycloheximide on oxidized tryptophan inducible CYP1A1 mRNA, protein, and EROD activity in Hepa-1 cells. The results demonstrate that combined exposure of wild-type Hepa-1 cells to either UV- or ozone-oxidized tryptophan and cycloheximide causes an increase in CYP1A1 mRNA, protein, and EROD activity, which is greater than the sum of the increases that were observed by exposure to each compound alone. The increase in EROD activity is dependent upon the dose and duration of cycloheximide treatment and is prolonged by actinomycin D when the latter compound was administered after removal of cycloheximide. Studies carried out to investigate the mechanism of this superinduction using various mutants of Hepa-1 cells, which are defective in either the AhR or AhR nuclear translocator protein indicated that the superinduction of oxidized tryptophan inducible EROD activity by cycloheximide occurs through the AhR. This is the first demonstration that oxidized tryptophan, in the presence of cycloheximide, causes superinduction of transcription of the Cyp1a1 gene with concomitant increase of CYP1A1 protein and EROD activity in Hepa-1 cells.
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PMID:Superinduction of Oxidized Tryptophan-Inducible Cytochrome P450 1A1 by Cycloheximide in Hepa lclc7 Cells. 1089 65

A functional cytochrome P4501A1 (CYP1A1) enzyme has been suggested to metabolize endogenous substrates and to autoregulate its own transcription in mouse hepatoma cells. In the present study, the regulation of CYP1A1 gene transcription by 6-formylindolo[3,2-b]carbazole (FICZ), a suggested endogenous ligand for the aryl hydrocarbon receptor (AhR), has been studied in mouse Hepa-1 cell lines. The tryptophan photoproduct, FICZ, has previously been characterized to possess very high AhR binding affinity and to transiently induce CYP1A1 gene expression in cultured cells at picomolar concentrations. The results from this study show that a transient induction of CYP1A1 mRNA at a low concentration of FICZ was only seen in wild-type cells. In c37 cells, deficient in CYP1A1, FICZ caused a sustained induction. Interestingly, we found that a higher amount of tryptophan in culture medium increased the constitutive level of CYP1A1 mRNA expression in the c37 cells but not in the wild-type cells. This suggests that a tryptophan-derived AhR ligand in the medium regulates the basal CYP1A1 expression. In metabolism studies performed with S9 prepared from c37 cells no metabolites were formed from FICZ and no loss of FICZ was observed, while with wild-type cells FICZ was rapidly metabolized. HPLC analysis revealed that at least three metabolites were formed in an NADPH-dependent manner from FICZ when incubated with rat liver S9. The CYP1A1 inhibitor ellipticine totally blocked the metabolism of FICZ. Ellipticine also enhanced both basal and FICZ-induced CYP1A1 mRNA expression. Taken together, these results indicate that tryptophan is a precursor of the endogenous ligand and that the suggested tryptophan-derived ligand FICZ is a substrate for the CYP1A1 enzyme and is involved in autoregulation of CYP1A1 transcription.
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PMID:Regulation of CYP1A1 transcription via the metabolism of the tryptophan-derived 6-formylindolo[3,2-b]carbazole. 1109 81

2-Amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD; EC 4.1.1.45) is one of the important enzymes regulating tryptophan-niacin metabolism. In the present study, we purified the enzyme from rat liver and kidney, and cloned the cDNA encoding rat ACMSD. The molecular masses of rat ACMSDs purified from the liver and kidney were both estimated to be 39 kDa by SDS/PAGE. Analysis of N-terminal amino acid sequences showed that these two ACMSDs share the same sequence. An expressed sequence tag (EST) of the mouse cited from the DNA database was found to be identical with this N-terminal sequence. Reverse transcription-PCR (RT-PCR) was performed using synthetic oligonucleotide primers having the partial sequences of the EST, and then cDNAs encoding rat ACMSDs were isolated by using subsequent 3'-rapid amplification of cDNA ends and RT-PCR methods. ACMSD cDNAs isolated from liver and kidney were shown to be identical, consisting of a 1008 bp open reading frame (ORF) encoding 336 amino acid residues with a molecular mass of 38091 Da. The rat ACMSD ORF was inserted into a mammalian expression vector, before transfection into human hepatoma HepG2 cells. The transfected cells expressed ACMSD activity, whereas the enzyme activity was not detected in uninfected parental HepG2 cells. The distribution of ACMSD mRNA expression in various tissues was investigated in the rat by RT-PCR. ACMSD was expressed in the liver and kidney, but not in the other principal organs examined.
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PMID:Purification and molecular cloning of rat 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase. 1180 86

Persistent infection with hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. All treatments known so far rely on the antiviral activity of interferon alfa (IFN-alpha) that is given alone or in combination with ribavirin. Unfortunately, only a fraction of the patients clear the virus during therapy and for those who do not respond there is currently no alternative treatment. Selectable subgenomic HCV RNAs (replicons) have been recently used to investigate the effect of IFN-alpha on HCV replication. However, it has not yet been analyzed whether other cytokines also play a role in the innate immune response against HCV. Here we show that IFN-gamma inhibits protein synthesis and RNA replication of subgenomic and genomic HCV replicons. We further show that the inhibitory action of IFN-gamma does not rely on the production of nitric oxide or the depletion of tryptophan. In conclusion, our results suggest that cytotoxic T cells and natural killer cells may contribute to HCV clearance not only by cell killing but also by producing IFN-gamma, thereby enhancing the intracellular inhibition of viral replication.
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PMID:Interferon-gamma inhibits replication of subgenomic and genomic hepatitis C virus RNAs. 1187 Mar 86

1. Without the addition of xenobiotics, only by changing the culture medium can one induce extensively and transiently cytochrome P4501A1 (CYP1A1) protein and mRNA in human hepatoma HepG2 cells. The induction was aryl hydrocarbon receptor (AhR)-dependent, and was proven by: (1) the medium change activated the AhR, as judged by a electrophoretic mobility shift assay; and (2) the AhR inhibitor alpha-naphthoflavone inhibited the medium change-mediated induction. 2. Induction of CYP1A1 was related to medium prepared by autoclaving. By screening the ingredients in the medium, the serum had no effect on CYP1A1 induction, whereas both photo-oxidized and autoclaved tryptophan were shown to induce CYP1A1, as indicated by CYP1A1 protein or ethoxyresorufin-O-deethylase activity. The autoclaved tryptophan contained in an autoclavable medium was a more potent inducer of CYP1A1 than photo-oxidized tryptophan. 3. The results provide some practical suggestions with experiments related to CYP1A1.
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PMID:Induction of cytochrome P4501A1 by autoclavable culture medium change in HepG2 cells. 1248 32

Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, is induced under various pathological conditions, including viral and bacterial infection, allograft rejection, cerebral ischemia, and tumor growth. We have previously reported that the expression of IDO mRNA was increased in some clinical cases of hepatocellular carcinoma in which the recurrence-free survival rate in these IDO-positive patients was significantly higher than that in patients without IDO mRNA induction in tumors. Additionally, IDO expressed in tumors was localized not to the tumor cells but instead to tumor-infiltrating cells by immunohistochemistry. In this study, in order to elucidate the mechanisms underlying anti-tumor effect of IDO, we investigated whether IDO inhibitor (1-methyl-dl-tryptophan, 1MT) affects the growth of subcutaneous B16 tumors in mice. Subsequently, the activity of natural killer (NK) cells was investigated under the conditions of inhibited IDO activity in vivo and in vitro. IDO mRNA expression of B16 cells, B16 subcutaneous tumor, sprenocytes of mice, and human NK cells were studied by reverse transcription-polymerase chain reaction. B16 subcutaneous tumor growth with or without IDO inhibition was observed and cytotoxic activity of NK cells were investigated under the conditions of inhibited IDO activity in vivo and in vitro. IDO mRNA was expressed in B16 subcutaneous tumor, splenocytes of tumor bearing mice, co-cultured splenocytes with B16, and human NK cells. On day 14, after injection of B16 melanoma cells, the sizes of tumors in IDO-inhibited mice were significantly larger than those in control mice. The cytotoxic activity of mice NK cells was reduced by IDO inhibition in vivo. In vitro inhibition of IDO, NK activity was reduced in dose-dependent manner of 1MT. In conclusion, these results indicated that IDO plays an important role in anti-tumor immunity by regulating cytotoxic activity of NK cells.
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PMID:Inhibition of indoleamine 2,3-dioxygenase suppresses NK cell activity and accelerates tumor growth. 1467 22

The presence of high affinity ligands for the aryl hydrocarbon receptor (AhR) in cell culture medium has generally been overlooked. Such compounds may confound mechanistic studies of the important AhR regulatory network. Numerous reports have described that light exposed cell culture medium induces AhR-dependent activity. In this study, we aimed at identifying the causative substance(s). A three-dimensional factorial design was used to study how the background activity of CYP1A1 in a rat hepatoma cell line (MH1C1) was controlled by photoproducts formed in the medium exposed to normal laboratory light. The light induced activity was found to be tryptophan dependent, but independent of riboflavin and other components in the medium. The light exposed medium showed the same transient enzyme inducing activity in vitro as the AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ). This substance, which we have previously identified as being formed in UV-exposed tryptophan solutions, is a substrate for CYP1A1 and it has a higher AhR binding affinity than TCDD. Several tryptophan related photoproducts were detected in the light-exposed medium. For the first time one of the formed photoproducts was identified as FICZ with bioassay driven fractionation coupled with HPLC/MS. These results clearly show that tryptophan derived AhR ligands, which have been suggested to be endogenous AhR ligands, influence the background levels of CYP1A1 activity in cells in culture.
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PMID:Identification of the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole, in cell culture medium, as a factor that controls the background aryl hydrocarbon receptor activity. 1578 23

Niacin (nicotinic acid and nicotinamide) is a vitamin used as a source of the NAD+ and NADP+ coenzymes required for many metabolic processes. Its low dietary levels induce the development of pellagra. Niacin has been used for decades in the treatment of patients with disturbed lipid and lipoprotein metabolism, this being the main cause of atherosclerotic changes in cardiovascular diseases. It is still the most efficacious drug in terms of its ability to increase HDL cholesterol content accompanied by a decrease in all atherogenic lipoproteins (VLDL, LDL, and L(a)) as well as fatty acids and triglycerides. Niacin also increases adiponectin level, which might result in additional atheroprotection. There are studies confirming the beneficial action of niacin against migraine and hyperphosphatemia associated with renal failure, ethanol-induced neurodegeneration, and loss of beta-cell function in type 1 diabetes. Moreover, it augments plasma tryptophan concentrations in HIV-infected patients and thyroid radiosensitivity to 131I. Inhibition of the invasion of hepatoma cells has also been proven. However, it is necessary to point out that the currently applied niacin preparations might exhibit such side effects as cutaneous flushing, gastrointestinal disturbances, and hepatotoxicity, particularly during treatment with sustained-release niacin preparations. The recent discovery of the G-protein-coupled receptor GPR109A, which mediates the antilipolytic effects induced by nicotinic acid in adipocytes as well as cutaneous vasodilation, allows the development of new agents interacting with this receptor. In view of these observations, niacin therapy must be accompanied by control of the choice of niacin preparation and its dose in order to eliminate or at least limit its side effects.
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PMID:[Niacin in therapy]. 1755 32


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