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)

Cytochrome P450 1A1 (CYP1A1), like many monooxygenases, can produce reactive oxygen species during its catalytic cycle. Apart from the well-characterized xenobiotic-elicited induction, the regulatory mechanisms involved in the control of the steady-state activity of CYP1A1 have not been elucidated. We show here that reactive oxygen species generated from the activity of CYP1A1 limit the levels of induced CYP1A1 mRNAs. The mechanism involves the repression of the CYP1A1 gene promoter activity in a negative-feedback autoregulatory loop. Indeed, increasing the CYP1A1 activity by transfecting CYP1A1 expression vectors into hepatoma cells elicited an oxidative stress and led to the repression of a reporter gene driven by the CYP1A1 gene promoter. This negative autoregulation is abolished by ellipticine (an inhibitor of CYP1A1) and by catalase (which catalyzes H(2)O(2) catabolism), thus implying that H(2)O(2) is an intermediate. Down-regulation is also abolished by the mutation of the proximal nuclear factor I (NFI) site in the promoter. The transactivating domain of NFI/CTF was found to act in synergy with the arylhydrocarbon receptor pathway during the induction of CYP1A1 by 2,3,7,8-tetrachloro-p-dibenzodioxin. Using an NFI/CTF-Gal4 fusion, we show that NFI/CTF transactivating function is decreased by a high activity of CYP1A1. This regulation is also abolished by catalase or ellipticine. Consistently, the transactivating function of NFI/CTF is repressed in cells treated with H(2)O(2), a novel finding indicating that the transactivating domain of a transcription factor can be targeted by oxidative stress. In conclusion, an autoregulatory loop leads to the fine tuning of the CYP1A1 gene expression through the down-regulation of NFI activity by CYP1A1-based H(2)O(2) production. This mechanism allows a limitation of the potentially toxic CYP1A1 activity within the cell.
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PMID:An autoregulatory loop controlling CYP1A1 gene expression: role of H(2)O(2) and NFI. 1049 Jun 21

We investigated the effect of resveratrol, a constituent of the human diet that has been shown to inhibit aryl hydrocarbon-induced carcinogenesis in animals, on the carcinogen activation pathway regulated by the aryl hydrocarbon receptor. Resveratrol inhibited the metabolism of the environmental aryl hydrocarbon benzo[a]pyrene (B[a]P) catalyzed by microsomes isolated from B[a]P-treated human hepatoma HepG2 cells. Resveratrol competitively inhibited, in a concentration-dependent manner, the activity of the carcinogen activating enzymes cytochrome P-450 (CYP)1A1/CYP1A2 in microsomes and intact HepG2 cells. Resveratrol inhibited the B[a]P-induced expression of the CYP1A1 gene, as measured at the mRNA and transcriptional levels. Resveratrol abolished the binding of B[a]P-activated nuclear aryl hydrocarbon receptor to the xenobiotic-responsive element of the CYP1A1 promoter but did not itself bind to the receptor. Resveratrol was also effective in inhibiting CYP1A1 transcription induced by the aryl hydrocarbon dimethylbenz[a]anthracene in human mammary carcinoma MCF-7 cells. These data demonstrate that resveratrol inhibits aryl hydrocarbon-induced CYP1A activity in vitro by directly inhibiting CYP1A1/1A2 enzyme activity and by inhibiting the signal transduction pathway that up-regulates the expression of carcinogen activating enzymes. These activities may be an important part of the chemopreventive activity of resveratrol in vivo.
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PMID:Inhibition of aryl hydrocarbon-induced cytochrome P-450 1A1 enzyme activity and CYP1A1 expression by resveratrol. 1049 59

The correlation between enzyme induction and cell proliferation caused by inducers of xenobiotic metabolizing enzymes was studied using a cell culture expressing a constitutive level of cytochrome P450 (hepatoma McA RH 7777) and a cell culture in which cytochrome P450 was absent (hepatoma 27). In hepatoma 27 cells, the inducers did not induce the synthesis of xenobiotic metabolizing enzymes but stimulated cell proliferation. Thus, the processes of signal transduction for enzyme induction and for cell proliferation by the inducers are different.
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PMID:Different pathways for mitogenic and enzyme induction signal transduction by cytochrome P450 inducers. 1049 10

We have used polycyclic aromatic hydrocarbon (PAH) alkyne metabolism-based inhibitors to test whether CYP1B1 metabolism is linked to aryl hydrocarbon receptor (AhR) activation in mouse embryo fibroblasts (MEF). 1-ethynylpyrene (1EP) selectively inactivated CYP1B1 dimethylbenzanthracene (DMBA) metabolism in C3H10T1/2 MEFs; whereas 1-(1-propynyl)pyrene (1PP) preferentially inhibited CYP1A1 activity in Hepa-1c1c7 mouse hepatoma cells (Hepa). In each cell type >90% inhibition of DMBA metabolism after 1 h treatment with each inhibitor (0.1 microM) was progressively reversed and then increased to levels seen with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induction (fourfold stimulation). It was found that 0.1 microM 1EP and 1PP maximally induce CYP1B1 and CYP1A1 mRNA levels in10T1/2 and Hepa cells, respectively, after 6 h. 1-Ethylpyrene (EtP), which lacks the activatable acetylene moiety, was far less effective as an inhibitor and as an inducer. AhR activation is essential for 1EP induction as evidenced by the use of AhR antagonists and AhR-deficient MEFs and absence of induction following inhibition of DMBA metabolism with carbon monoxide (CO). Inhibition of CYP1B1 was linked to enhanced AhR activation even at early stages prior to significant ligand depletion. 1EP and EtP were similarly effective in stimulating AhR nuclear translocation, though 5-10 times slower compared with TCDD, and produced no significant down-regulation of the AhR. TCDD activated AhR/Arnt complex formation with an oligonucleotide xenobiotic response element far more extensively than 1EP or EtP, even at concentrations of 1EP that increased CYP1B1 mRNA to similar levels. CO did not influence these responses to EtP, event hough CO treatment potentiated EtP induction of CYP1B1 mRNA. These differences suggest a fundamental difference between PAH/AhR and TCDD/AhR complexes where CYP1B1 metabolic activity regulates the potency, rather than the formation of the AhR/Arnt complex.
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PMID:Metabolism-based polycyclic aromatic acetylene inhibition of CYP1B1 in 10T1/2 cells potentiates aryl hydrocarbon receptor activity. 1058 Dec 6

Procarcinogenic polycyclic aromatic hydrocarbons (PAHs) induce their own metabolism and activation by binding to the cytosolic aryl hydrocarbon receptor (AhR), which then translocates to the nucleus and activates CYP1A1 gene transcription via xenobiotic response elements (XREs). Although the AhR demonstrates a strict specificity for planar aromatics, nonplanar (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene also induced CYP1A1 expression in HepG2 cells over a delayed timecourse (approximately 6-12 h), suggesting a requirement for (+/-)trans-7,8-dihydrobenzo(a)pyrene metabolism. Aldo-keto reductase (AKR) inhibitors blocked this effect, suggesting that benzo(a)pyrene-7,8-dione (BPQ), a planar PAH o-quinone generated by AKRs, was the downstream inducer. BPQ was found to be a potent and rapid inducer of CYP1A1, with an EC50 value in HepG2 cells identical to that of the parent benzo(a)pyrene. BPQ was a more potent inducer of CYP1A1 when compared with the 1,6-, 3,6-, and 6,12-benzo(a)pyrene-diones. Multiple PAH o-quinones caused induction of CYP1A1, demonstrating that this was a general property of AKR-generated PAH o-quinones. HepG2-101L cells stably transfected with a XRE-luciferase construct showed that BPQ activated CYP1A1 transcription via a XRE-dependent mechanism. BPQ failed to induce CYP1A1 in AhR-deficient and AhR nuclear translocator-deficient murine hepatoma cell lines and confirmed that induction of CYP1A1 was AhR and AhR nuclear translocator-dependent. Electrophoretic mobility shift assays demonstrated the specific appearance of BPQ-activated AhR in the nucleus, and immunofluorescence studies confirmed that BPQ mediated nuclear translocation of the AhR. Classical bifunctional inducers elevate CYP1A1 expression via a XRE and are subsequently converted by CYP1A1 to electrophiles that induce phase II enzymes via an electrophilic response element/antioxidant response element PAH o-quinones represent a novel class of bifunctional inducer because they are electrophiles produced by phase II enzymes that simultaneously induce phase I enzymes via a XRE and phase II enzymes via a electrophilic response element/antioxidant response element (see also M. E. Burczynski et al., Cancer Res., 59: 607-614, 1999). This study shows that the AhR provides the only known mechanism by which genotoxic PAH o-quinones generated in the cytosol can be targeted to the nucleus with specificity.
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PMID:Genotoxic polycyclic aromatic hydrocarbon ortho-quinones generated by aldo-keto reductases induce CYP1A1 via nuclear translocation of the aryl hydrocarbon receptor. 1070 4

Alachlor, metolachlor, and propachlor are widely used chloroacetanilide herbicides. Their cytotoxicity in rat (Fa32) and human (Hep G2) hepatoma-derived cells was investigated, in connection with their influence on the endogenous glutathione (GSH) content, on the xenobiotic-metabolizing phase I enzymes 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depentylase (PROD), and phase II glutathione transferase (GST). The cytotoxicity was measured by the neutral red uptake inhibition assay. The following toxicity range was observed in both cell lines: propachlor > alachlor > metolachlor. When the endogenous GSH content was reduced by pretreatment of the cells with L-buthionine (S,R)-sulfoximine, the cytotoxicity of the herbicides increased strongly in both cell lines. EROD and PROD activities were dose-dependently increased to different degrees in Fa32, as was EROD in Hep G2, but no PROD activity was observed in these cells. The GSH content was not altered after 1 h treatment, and was approximately doubled after 24 h. GST activity was increased in Fa32 cells but not in Hep G2. A comparable cytotoxicity was observed for the investigated chloroacetanilides in both the rat and the human cell lines. Different interactions with xenobiotic-metabolizing phase I and II enzymes were observed, and GSH showed a protective effect against the acetanilides in both cell lines.
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PMID:Glutathione-dependent cytotoxicity of the chloroacetanilide herbicides alachlor, metolachlor, and propachlor in rat and human hepatoma-derived cultured cells. 1081 65

The gene encoding the xenobiotic-metabolising microsomal enzyme, epoxide hydrolase (mEPHX), shows two common mutations, i.e. at exons 3 and 4. It is unknown how these genetic polymorphisms relate to risk of developing alcoholic liver disease (ALD) and/or hepatocellular carcinoma (HCC) in a Caucasian population. DNA samples extracted from the blood of 61 ALD patients and 203 healthy controls, and from archival liver tissue of 46 cases of HCC, were subjected to polymerase chain reaction amplification followed by digestion with EcoR V or Rsa I to demonstrate polymorphisms of exon 3 or 4, respectively. The distributions of the genotypes of exon 3 in the ALD and HCC patients, and exon 4 in the HCC patients did not differ significantly from those of the control group. However, compared with the control group, the ALD group contained a significantly greater number of individuals homozygous or heterozygous for the exon 4 mutation. This suggested association between possession of the exon 4 mutant mEPHX allele and increased risk of developing ALD may relate to known interactions between mEPHX and alcohol-metabolising enzyme systems, or to linkage disequilibrium between the mutation and other genetic risk factors for ALD.
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PMID:Polymorphisms of the gene for microsomal epoxide hydrolase and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a Caucasian population. 1081 27

Nuclear receptors constitute a large family of ligand-modulated transcription factors that mediate cellular responses to small lipophilic molecules, including steroids, retinoids, fatty acids, and exogenous ligands. Orphan nuclear receptors with no known endogenous ligands have been discovered to regulate drug-mediated induction of cytochromes P450 (CYP), the major drug-metabolizing enzymes. Here, we report the cloning of an orphan nuclear receptor from chicken, termed chicken xenobiotic receptor (CXR), that is closely related to two mammalian xenobiotic-activated receptors, the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Expression of CXR is restricted to tissues where drug induction of CYPs predominantly occurs, namely liver, kidney, small intestine, and colon. Furthermore, CXR binds to a previously identified phenobarbital-responsive enhancer unit (PBRU) in the 5'-flanking region of the chicken CYP2H1 gene. A variety of drugs, steroids, and chemicals activate CXR in CV-1 monkey cell transactivation assays. The same agents induce PBRU-dependent reporter gene expression and CYP2H1 transcription in a chicken hepatoma cell line. These results provide convincing evidence for a major role of CXR in the regulation of CYP2H1 and add a member to the family of xenobiotic-activated orphan nuclear receptors.
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PMID:CXR, a chicken xenobiotic-sensing orphan nuclear receptor, is related to both mammalian pregnane X receptor (PXR) and constitutive androstane receptor (CAR). 1100 56

Hepatoma cells show alterations in the response to oxidative stress (decreased lipid peroxidation) and in xenobiotic metabolism enzymes (decreased P450, increased GST and ALDH3). This study examined the effect of lipid peroxidation on the expression of the above enzymes in two rat hepatoma cell lines (MH(1)C(1) and 7777). To induce oxidative stress, cells were exposed to arachidonic acid (to increase lipid peroxidation substrate) and/or to beta-naphthoflavone (to increase CYP450), and treated with one dose of iron/histidine. The cells, that were still viable after the challenge, were refed with the culture medium and CYP1A1, GST, and ALDH3 enzymes monitored for 1, 6, 12, and 24 h. Treatments that increased markers indicative of lipid peroxidation are associated with a decrease in enzyme activities, which was permanent for CYP1A1 and transient for the other enzymes. We speculate from these data that aldehydic byproducts of lipid peroxidation may be responsible for these effects. Thus, restoration of lipid peroxidation in hepatoma cells seems to induce a rapid adaptation to oxidative stress, which is achieved by a simultaneous decrease of reactive oxygen species production and an increase in the two main enzymes involved in the removal of the aldehydic products of lipid peroxidation.
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PMID:Changes of CYP1A1, GST, and ALDH3 enzymes in hepatoma cell lines undergoing enhanced lipid peroxidation. 1112 27

Activities of enzymes of active oxygen forms detoxication and phase II xenobiotic metabolism were measured in rat hepatoma 27 cells transplanted to different organs. Activity of phase II xenobiotic metabolizing enzymes was higher in hepatoma cells growing subcutaneously than in those transplanted into the liver, while activity of active oxygen forms detoxication enzymes (except catalase) was higher in cells transplanted into the liver. Benz(a)pyrene induced the enzyme activities in hepatoma growing both subcutaneously and in the liver.
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PMID:Activity of detoxication enzymes in rat hepatoma 27 transplanted in different organs. 1118 30


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