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)

The lack of aryl hydrocarbon (benzo[a]pyrene) hydroxylase (AHH) (EC 1.14.14.1) induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a clone of rat hepatoma (HTC cl-1) cells is not caused by the lack of nuclear Ah receptor or by a deficiency in the activity of NADPH-cytochrome c (P-450) reductase. Treatment of HTC cl-1 cell line with TCDD for 18 h in culture resulted in a reproducible 500-600% increase in reductase activity without concomitant expression in AHH activity. These data suggests that TCDD induces cytochrome c reductase activity and that the lack of inducible AHH activity in rat hepatoma cells could reflect a defect in the structural gene (s) encoding for cytochrome P1-450, or an Ah receptor with a faulty DNA binding domain.
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PMID:Evidence that 2,3,7,8-tetrachlorodibenzo-p-dioxin induces NADPH cytochrome c (P-450) reductase in rat hepatoma cells in culture. 339 76

Analysis of male Sprague--Dawley rat hepatic cytosol from two commercial animal laboratories for the polycyclic aromatic hydrocarbon (PAH) 4-5S binding protein showed that in one group of animals no 4-5S protein was detectable (-4S) whereas the levels of this protein were 208 +/- 57 fmol/mg cytosolic protein in the +4S rats. The role of the 4-5S binding protein in the transregulation of the cytochrome P-450-dependent monooxygenase, aryl hydrocarbon hydroxylase (AHH), was therefore investigated in the -4S and +4S Sprague-Dawley rats. The dose-response curves for the induction of hepatic microsomal AHH by 3-methylcholanthrene (MC) were indistinguishable in both +4S and -4S rats and comparable results were observed for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as an inducer. Both MC and TCDD exhibit high binding affinities for the aryl hydrocarbon (Ah) 8-9S receptor protein, whereas MC but not TCDD bound with high affinity to the 4-5S binding protein. Benzo[a]pyrene (B[a]P) binds with moderate affinity to both the Ah receptor and 4-5S binding protein and induces AHH in both -4S and +4S rats. Perylene binds with moderate affinity to the 4-5S binding protein but does not interact with the Ah receptor. This PAH was inactive as an inducer of AHH in +4S and -4S Sprague-Dawley rats. These results show that there was a correlation between the Ah receptor binding affinities of MC, B[a]P and perylene and their potencies as AHH inducers in Sprague-Dawley rats, and this corresponds to previous correlations for the induction of AHH in rat hepatoma H-4-II E cells in culture. In contrast no such correlations existed between the AHH induction potencies of these polynuclear aromatic hydrocarbons and their affinities for the 4-5S binding protein. These data, coupled with the fact that the absence of the 4-5S binding protein in the -4S Sprague-Dawley rats did not affect AHH inducibility by MC, B[a]P or perylene, suggests that the 4-5S binding protein does not play a role in the transregulation of cytochrome P-4501A1 in the rat or rat hepatoma cells in culture.
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PMID:Role of the 4-5S binding protein in the induction of aryl hydrocarbon hydroxylase in the rat. 340 44

To examine the transcriptional regulation of the human cytochrome P450IA1 gene, a 3574 bp fragment containing 1140 bp of 5' flanking sequences, exon 1 (leader information only), intron 1, and the leader sequences from exon 2, was cloned upstream of the reporter gene, chloramphenicol acetyltransferase, and used to transfect the human hepatoma cell line, HepG2. In transient expression assays, treatment of the transfected cells with 3-methylcholanthrene, benzo[a]pyrene or 2,3,7,8-tetrachlorodibenzofuran was shown to induce the expression of chloramphenicol acetyltransferase 10-fold. Previous studies by other investigators have identified a xenobiotic responsive element at greater than 800 bp 5' to the cap site in the mouse and rat cytochrome P450IA1 gene. In the current report, deletion of sequences from the 5' side of the P450IA1 fragment, as well as internal deletions, were used to identify at least three additional regulatory elements. A second positive, 3-methylcholanthrene responsive element was localized to sequences between -49 and -560 in addition to confirming the location of a similar element between -831 and -1140. These elements flank a potent negative regulatory element that has been conserved between the rat, mouse and human P450IA1 genes and also exhibits significant sequence identity with one of the negative control elements of the human c-Ha-ras1 proto-oncogene. Deletion of the negative control element clearly demonstrated that the fragments containing xenobiotic responsive elements also possess positive, constitutive control activity. A fourth element located within intron 1 was shown to potentiate the activity of 3-methylcholanthrene when the cells were treated simultaneously with the glucocorticoid agonist, dexamethasone.
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PMID:Identification of multiple regulatory elements on the human cytochrome P450IA1 gene. 340 63

In cultures of the differentiated clones Faza 967, Fao and HF, derived from Reuber hepatoma, physiological doses of glucocorticoid induce chenodeoxycholate 6 beta-hydroxylation, a microsomal cytochrome-P-450-mediated activity (enhanced in liver by phenobarbital and not by benzo[a]anthracene). Whereas 12-O-tetradecanoylphorbol 13-acetate (TPA) alone has no effect the tumor promoter, when added to dexamethasone, enhances this induction. This enhancement, half-maximum with 10 ng/ml TPA, is a function of the dose between 1 ng/ml and 50 ng/ml; 50 ng/ml (80 nM) increase 4-7-fold the induction rate (as measured in cultures by the amount of bile acid hydroxylated per 10(6) cells in 24 h, and in homogenates from treated cells) and 2.5-fold the maximum activity attained by the third day of induction. When added to cultures of the dedifferentiated clone H5, treated with benzo[a]anthracene, TPA does not influence benzo[a]pyrene hydroxylase induction, as shown by the total and relative amounts of the various hydrosoluble benzo[a]pyrene metabolites. TPA does not affect tyrosine aminotransferase induction in dexamethasone-treated Fao cultures. The enhancement is not suppressed by indomethacin, an inhibitor of prostaglandin synthesis. After dexamethasone removal from induced Faza 967 cultures, addition of TPA to the medium does not affect the decay rate of the chenodeoxycholate-hydroxylating activity. Retinoic acid similarly enhances the induction by dexamethasone of chenodeoxycholate hydroxylation, both in treated Faza 967 cultures and in homogenates from treated cultures. The effects of TPA and retinoic acid are additive. These results suggest a possible cooperation at the transcriptional level between transactive factors, involving TPA-mediated alterations, retinoic acid and glucocorticoid receptors. The system described might provide a convenient experimental approach in the study of its mechanism.
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PMID:Enhancing effect of a phorbol ester and of retinoic acid on glucocorticoid induction of chenodeoxycholate hydroxylation in hepatoma cultures. 340 83

Transcription of the drug-metabolizing cytochrome P-450c gene is induced by 3-methylcholanthrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Previously, we defined two xenobiotic responsive elements (XREs) of approximately equal to 15 base pairs, both of which activate transcription in cis in response to these xenobiotics. Using a gel mobility shift assay, we have identified a factor that specifically binds to the XREs. This factor appears in nuclei of mouse hepatoma cell line Hepa-1 only when the cells are treated with the xenobiotics, while the factor is undetectable in the nuclei of a 3-methylcholanthrene-treated mutant of Hepa-1 with defective function of a xenobiotic receptor. In addition, the nuclear factor bound to the XRE in the gel was found to be associated with [3H]TCDD when the cells were treated with it, suggesting that the xenobiotic receptor is at least a component of the DNA-binding factor. The cytoplasmic fraction from nontreated Hepa-1 cells also contains the factor as a cryptic form and prominently reveals its DNA-binding activity by incubation with 3-methylcholanthrene in vitro. These results not only suggest the involvement of the XRE-binding factor in transcriptional activation via XREs but also provide evidence that the binding of ligands to the preexisting factor in a cryptic form induces its XRE-binding activity, which is probably followed by its translocation from cytoplasm to nucleus.
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PMID:A DNA-binding factor specific for xenobiotic responsive elements of P-450c gene exists as a cryptic form in cytoplasm: its possible translocation to nucleus. 341 62

HLp is a human liver cytochrome P-450 that is immunochemically related to the glucocorticoid-inducible liver cytochrome P-450p in the rat and its homologue in the rabbit, P-450 LM3c. To investigate the structure and regulation of HLp, we used a monoclonal antibody that recognizes purified HLp to screen a human liver cDNA library in lambda gt11. We isolated and sequenced two overlapping cDNA clones that span the entire 2011 bases of an mRNA that codes for a protein of 504 amino acids. The predicted amino-terminal amino acid sequence of this protein is identical to the first 20 residues determined from purified HLp. HLp mRNA shares more than 70% sequence homology with related proteins from the rat and rabbit but less than 40% homology with other published cytochrome P-450 genes. Moreover, Southern blot analysis of human and rat genomic DNA revealed 50 and 60 kilobases of DNA, respectively, hybridizable to the HLp cDNAs. Blot analysis of human liver RNA from five patients revealed major (2.2 kilobase) and minor (3.0 kilobase) bands that hybridized to HLp cDNAs. The apparent concentration of these hybridizable mRNAs as well as the amounts of immunoreactive HLp protein in microsomes from the same liver were increased in a dose-dependent relationship in three patients who received dexamethasone, a potent glucocorticoid. Furthermore, in samples of RNA and of microsomes isolated from cultures of a human hepatoma cell line (Hep G2) incubated for 120 hr in medium containing dexamethasone, there was a 6-fold induction of the two mRNA species hybridizable to HLp cDNAs and a 3-fold induction of immunoreactive HLp protein as compared to the values for cultures incubated in steroid-free medium. We conclude that HLp is a human representative of a conserved glucocorticoid-inducible cytochrome P-450 gene family whose mechanism of induction involves accumulation of HLp mRNA.
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PMID:Complete cDNA sequence of a cytochrome P-450 inducible by glucocorticoids in human liver. 346 94

We have previously demonstrated the inducibility of both cytochrome P-448- and P-450-dependent monooxygenases in the differentiated rat hepatoma cell line MH1C1. Further experiments with these cells on the expression of different forms of cytochrome P-450, inducible not only by phenobarbital (PB) and 3-methylcholanthrene (MC), but also by metyrapone (MP), ethanol (E), and beta-naphthoflavone (BNF) are reported here. The effects of the in vitro addition of the inhibitors alpha-naphthoflavone and beta-naphthoflavone on the aryl hydroxylase activity (AHH) and the influence of protein synthesis on the induction of cytochrome P-450 were also assessed. Cultures were exposed to the inducers PB, MC, BNF, and MP during the last 6 days of culture and to E for 10 days. The inhibition of protein synthesis was obtained by adding cycloheximide (CY) to the cultured cells during the last 24 hr. The exposure of MH1C1 cells to various concentrations of MP resulted in a dose-dependent increase in AHH activity. The treatment of MH1C1 cells with different concentrations of ethanol produced a significant dose-dependent increase of monooxygenases. AHH activity, induced by the various treatments, was inhibited in a dose-dependent way by alpha-naphthoflavone and beta-naphthoflavone. Cy reduced the concentration of cytochrome P-450 and the AHH activity induced by the various treatments, thus indicating an implication of the protein synthesis in the mechanism(s) of induction.
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PMID:Biochemical properties of carcinogen-metabolizing enzymes in cultured hepatoma cells. 357 79

The induction of cytochrome P-450 (c+d) messenger RNAs in rat liver by 3-methyl cholanthrene follows a biphasic pattern. Administration of cycloheximide blocks the induction of cytochrome P-450 (c+d) messenger RNAs by 3-methylcholanthrene as well as cytochrome P-450 (b+e) messenger RNAs by Phenobarbitone. Transcription of these messenger RNAs in isolated nuclei is also blocked by cycloheximide administration. Thus cycloheximide not only fails to mimic the superinduction effects reported in hepatoma cell cultures, but actually blocks the specific transcription process. Exogenous hemin, while counteracting the effects of CoCl2 (heme biosynthetic inhibitor) on cytochrome (c+d) messenger RNA induction by the hydrocarbon, fails to counteract the effects of cycloheximide. It is suggested that a positive labile transcription factor is involved in the regulation of cytochrome P-450 gene expression in vivo.
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PMID:Differential effects of cycloheximide on rat liver cytochrome P-450 gene transcription in the whole animal and hepatoma cell culture. 368 89

In mouse hepatoma cells, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) stimulates cytochrome P1-450 gene transcription via the formation of TCDD-receptor complexes and the accumulation of the complexes in the nucleus. Here, we show that the DNA that flanks the 5'-end of the cytochrome P1-450 gene contains at least two discrete TCDD-responsive domains. Each domain has properties analogous to those of transcriptional enhancers. Each domain requires TCDD-receptor complexes for its function. There is no significant nucleotide sequence homology between the two TCDD-responsive domains.
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PMID:Control of gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Multiple dioxin-responsive domains 5'-ward of the cytochrome P1-450 gene. 370 Apr 11

Subcellular fractions of nuclei, mitochondria, endoplasmic reticulum, plasma membrane and cytosol were prepared from liver and hepatoma 7288CTC. Marker enzyme activities, biochemical compositions and electron microscopy were used to establish purity. Hepatoma NADH: cytochrome C reductase and 5'-nucleotidase exhibited abnormal subcellular distributions. The lipids from the subcellular fractions were examined in detail. Mitochondria and plasma membranes were characterized by elevated percentages of diphosphatidylglycerol and sphingomyelin, respectively, in both tissues. All hepatoma subcellular fractions contained dramatically elevated levels of sphingomyelin and cholesterol, two components that form preferential strong complexes in vitro. The fatty acid composition of hepatoma sphingomyelin differed markedly from liver and, unlike liver, did not exhibit organelle specific compositions. Some hepatoma lipid classes contained reduced percentages of palmitate while others contained higher levels. Hepatoma phosphatidylcholine and phosphatidylethanolamine from organelles contained lower percentages of long chain polyunsaturated fatty acids than liver. Generally, unique fatty acid profiles exhibited by individual phospholipid classes of liver subcellular fractions were absent or much reduced in the hepatoma. The ratios of oleate to vaccenate were near one for most of the phospholipid classes of most liver fractions, but all hepatoma classes, with few exceptions, contained a much higher percentage of oleate in all subcellular fractions. The hypothesis is proposed that the origin of some acyl moieties for the biosynthesis of various hepatoma lipid classes differs from liver sources. The possible changes in acyl pools, sources and compartments for complex lipid biosynthesis could result in change in the quantities of molecular species that could contribute to the abnormal properties of the hepatoma membranes.
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PMID:A comparison of lipids from liver and hepatoma subcellular membranes. 371 48


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