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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper reports the evidence for the existence of multiple sites of action of aflatoxin B1 in relation to its inhibition of rat hepatic nuclear RNA synthesis. Two hours after aflatoxin B1 injection (0.3 mg/100 g body weight), rat hepatic nuclear and nucleolar RNA synthesis, in vitro, were inhibited 70 and 90% respectively. When total nuclear free and engaged RNA polymerases were solubilized and assayed in the presence of alpha-amanitin (3.2 micrograms/ml), only alpha-amanitin-sensitive activity was reduced (50 to 70%) by aflatoxin B1. DEAE-Sephadex column chromatography confirmed this finding and further demonstrated that RNA polymerase II was the activity selectively inhibited. Since aflatoxin B1 dramatically inhibited nucleolar RNA synthesis, but had little effect on RNA polymerase I activity per se, it is concluded, therefore, that, in addition to its direct inhibitory effect on the enzymic function of RNA polymerase II, aflatoxin B1 must also cause impairment of the nucleolar DNA template function.
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PMID:Mechanism of aflatoxin B1 inhibition of rat hepatic nuclear RNA synthesis. 86 81

Microsomes prepared from rats pre-treated with phenobarbitone are more effective in activating aflatoxin B1 in vitro to a metabolite which inhibits RNA polymerase than are microsomes obtained from control animals. This result is in contrast with the situation in vivo where pre-treatment with phenobarbitone protects against inhibition of RNA synthesis by aflatoxin B1. The hypothesis is advanced that, in vivo, the activation of aflatoxin B1 which is significant in terms of inhibition of nucleic acid synthesis largely occurs on the outer nuclear membrane, and that by increasing activation by the microsomes, phenobarbitone pre-treatment reduces the amount of aflatoxin B1 available for the nuclear activation.
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PMID:The effect of pre-treatment with phenobarbitone on the activation of aflatoxin B1 by rat liver. 95 46

The mouse compared with the rat, is more resistent to the acute toxic action of aflatoxin B1 and is refractory to its hepatocarcinogenic properties. Aflatoxin B1 inhibits DNA synthesis more strongly than RNA synthesis in the rat, and both nucleic acid syntheses more strongly in rat than in the mouse. Mouse hepatic microsomes, like those of the rat, are capable of metabolizing aflatoxin B1 in vitro in the presence of NADPH, to an active form which binds to DNA both in solution and in intact nuclei and also inhibits nuclear RNA synthesis. Non NADPH-dependent binding of aflatoxin B1 to nuclei is not effective in inhibiting RNA polymerase and is largely removed by washing with lipid solvents. Mouse nuclear RNA polymerases particularly Mn 2+ (NH4)2SO4 primed acitivity are more resistant to inhibition in vitro by activated aflatoxin B1 than are the corresponding enzyme activities in rat liver nuclei. This would appear to be due to the bound aflatoxin B1 being less efficient in the case of the mouse nucleus, in inhibiting RNA synthesis. Mouse liver slices exhibit a much lesser degree of inhibition of RNA synthesis by aflatoxin B1 than do rat liver slices. Accompanying this is a lower level of binding of aflatoxin B1 to subcellular particulate fractions in the mouse liver slice compared to the rat, this disparity being most marked in the case of the nuclear fraction. The suggestion is made that the resistance of RNA synthesis in the mouse liver, to aflatoxin B1, and perhaps also resistance to its toxicity, is dependent, not on a lower capacity to activate the toxin, but (a) on a less efficient inhibition of RNA synthesis by nuclear bound toxin, and (b) a detoxifying mechanism at least partially situated in the cytosol fraction.
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PMID:Some studies of the effects of aflatoxin B1 in vivo and in vitro on nucleic acid synthesis in rat and mouse. 126 46

The effect of aflatoxin B1 (AFB1) on the template function for RNA synthesis of several single and double-stranded synthetic DNAs containing cytosine (C) and/or hypoxanthine (H) bases is studied in vitro. The results indicate that AFB1, after liver microsome activation, strongly inhibits the template function of poly[d(I-C)] and has little, if any, effect on polydI.polydC, polydI, or polydC. This conclusion is reached whether rat liver nuclear free RNA polymerase or E. coli RNA polymerase is used for the transcription. The mechanism of this inhibition is believed mainly due to the inhibition of elongation of RNA synthesis, because autoradiography of the [alpha-32 P]GTP labeled RNAs after polyacrylamide gel electrophoresis clearly shows that the size of the RNA from AFB1 treated group is dramatically reduced. The evidence that the selective inhibition of poly[d(I-C)] template function is a direct reflection of the binding of AFB1 to poly[d(I-C)] is provided by the use of radioactive [3H]AFB1 for the binding and by spectrum analysis of the appearance of a broad AFB1-DNA adduct peak between 300 nm and 400 nm right after the typical DNA peak at 260 nm. These data, which are in direct support to our recent report (F.L. Yu, et al., Carcinogenesis, 11, 475-478, 1990), suggest that the binding of AFB1 prefers alternating, double-stranded DNA, and the binding affinity of AFB1 to DNA is greatly reduced when the bases are in either single- or double-stranded homopolymer forms.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transcriptional effect of aflatoxin B1 on cytosine and/or hypoxanthine containing DNAs. 171 92

Previous studies suggested multiple sites of action of aflatoxin B1 (AFB1) in vivo to inhibit rat liver nuclear RNA synthesis--it impairs nucleolar DNA template function and inhibits RNA polymerase II activity. We have previously shown that AFB1 activated in vitro inhibits nucleolar RNA synthesis. The question is whether AFB1 can inhibit RNA polymerase II under these in vitro conditions. Male Sprague-Dawley rats, 200 g, were injected i.p. with 0.6 mg AFB1 and liver nuclei were isolated 2 h later. When the total nuclear free RNA polymerases were extracted and assayed in the absence and presence of alpha-amanitin (3.2 micrograms/ml), we found that only alpha-amanitin-sensitive (i.e., RNA polymerase II) activity was inhibited (97%). DEAE-Sephadex chromatography confirmed this result. When total nuclear free RNA polymerases were incubated with AFB1 activated in vitro under conditions producing 70% inhibition of nucleolar RNA synthesis, no inhibition was observed for either alpha-amanitin-sensitive or -resistant activities. Similar results were obtained with low and high (28 and 167 micrograms/ml) concentrations of AFB1. This was further confirmed using highly purified RNA polymerase II. We conclude that AFB1 inhibition of RNA polymerase II activity in vivo is not a result of direct interaction of AFB1 to the enzyme.
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PMID:Evidence for an indirect mechanism of aflatoxin B1 inhibition of rat liver nuclear RNA polymerase II activity in vivo. 241 4

The effect of aflatoxin B1 on the DNA template and DNA-dependent RNA polymerases in buffalo liver was studied. Aflatoxin B1 inhibited both Mg2+- and Mn2+-activated RNA polymerases in a dose-dependent manner. At 10 micrograms the inhibition of both enzymes was almost complete. The inhibitory effect on the solubilized enzymes was higher than the chromatin-bound, suggesting a direct effect at the enzyme level. On the other hand, incubating DNA or deoxyribonucleoprotein (DNP) with 2 micrograms aflatoxin reduces its transcriptional capacity with a greater effect on the Mg2+-activated RNA polymerase than the Mn2+-activated enzyme. These results suggest that aflatoxin B1 inhibits in vitro transcription in buffalo liver at both enzyme and template levels.
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PMID:In vitro effect of aflatoxin B1 on the transcriptional activity of DNA template, chromatin and soluble DNA-dependent RNA polymerases in buffalo liver. 312 97

In an earlier report, it was shown that aflatoxin B1 treatment strongly inhibits rat liver nucleolar RNA synthesis (Yu, F. L. (1977) J. Biol. Chem. 252, 3245-3251). The present paper is an attempt to elucidate the mechanism of this inhibition. Two h after aflatoxin B1 injection (0.3 mg/100 g body weight), rat liver nucleolar RNA synthesis, in vitro, was inhibited by an average of 90%. This inhibition could result from (a) inhibited RNA polymerase I activity per se, (b) impaired nucleolar DNA template, or (c) impaired nucleolar chromatin. Earlier studies found that the total RNA polymerase I activity was not affected by aflatoxin B1 treatment. In the present work the total nucleolar DNAs from control and from aflatoxin B1-treated groups were isolated and compared for template efficiencies in directing RNA synthesis with solubilized RNA polymerase I from the control group. No difference was found. However, when nucleolar chromatin function was analyzed, it was found that aflatoxin B1 treatment resulted in a dramatic reduction in the RNA chain elongation rate to only 13% of the control. The chain number, which is a measure of the number of engaged enzymes transcribing the nucleolar chromatin initiated in vivo, was only slightly reduced (33%). Furthermore since it was found that aflatoxin B1 treatment did not increase RNase activity in the treated nucleoli, the dramatic decrease in RNA chain elongation is therefore believed to be the major mechanism of aflatoxin B1 inhibition of rat liver nucleolar RNA synthesis. DNase I digestion of the nucleolar chromatin suggests that aflatoxin B1 treatment may have altered the conformation of the transcriptionally active regions of the nucleolar chromatin.
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PMID:Studies on the mechanism of aflatoxin B1 inhibition of rat liver nucleolar RNA synthesis. 616 44

The treatment of germinating maize seeds (cv. Ganga 2) with aflatoxin B1 resulted in suppression of ribonucleic acid (RNA), protein, and deoxyribonucleic acid (DNA) synthesis at 3, 4, and 5 h, respectively. At or below the concentrations inhibitory for these in vivo syntheses, the toxin inhibited chromatin-bound DNA-dependent RNA polymerase activity. The synthesis of both polyadenylated and non-polyadenylated RNA was inhibited, but the effect on the former was more pronounced. Equilibrium dialysis and difference spectral and viscometric analyses showed a binding of aflatoxin B1 to DNA isolated from the seeds. It is proposed that the inhibition of RNA synthesis in maize seeds by the toxin is due to the interference with the RNA polymerase activity, which seems, at least partially, due to the impairment of DNA template functions.
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PMID:Effect of aflatoxin B1 on chromatin-bound ribonucleic acid polymerase and nucleic acid and protein synthesis in germinating maize seeds. 617 Feb 58

The effect of methylazoxymethanol acetate on rat liver nuclear and nucleolar RNA synthesis is investigated at various doses (5 to 50 mg/100 g body weight) and for various lengths of time (1 to 24 hr). The results show that this carcinogen is a potent inhibitor of both nuclear and nucleolar RNA synthesis. Like other carcinogens studied previously in this laboratory, e.g., N-hydroxy-2-acetylaminofluorene, aflatoxin B1, and actinomycin D, methylazoxymethanol acetate inhibits RNA synthesis at multiple sites. It impairs chromatin template function and selectively inhibits the activity of RNA polymerase II. Experimental evidence suggests the mechanism of inhibition of RNA polymerase II activity is due to a decrease in catalytic efficiency rather than in the total number of the enzyme. In addition, it is found that methylazoxymethanol acetate induces a dramatic condensation of nucleoplasmic chromatin.
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PMID:Effect of methylazoxymethanol acetate on rat liver nuclear and nucleolar RNA synthesis. 618 91

The literature on various isolated carcinogen-DNA adducts indicates clearly that the binding of chemical carcinogens to DNA is highly specific. Since DNA in eukaryotic cells is complexed with chromosomal proteins and organized into transcriptionally active and inactive chromatin, chemical carcinogens also might show binding specificities at the chromatin level. Using Escherichia coli RNA polymerase and the endogenous engaged RNA polymerase I as specific probes to monitor respectively the physiologically inactive and active nucleolar chromatin template function, this paper reports that aflatoxin B1, after metabolic activation either in vivo or in vitro, binds preferentially to the physiologically active regions of rat liver nucleolar chromatin, and that this binding specificity is largely lost after the removal of chromosomal proteins from the nucleoli.
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PMID:Preferential binding of aflatoxin B1 to the transcriptionally active regions of rat liver nucleolar chromatin in vivo and in vitro. 640 39


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