Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of several naturally occurring and synthetic flavonoids on the metabolism of benzo(a)pyrene and aflatoxin B1 were evaluated. Addition of apigenin, chrysin, fisetin, flavonone, galangin, hesperitin, kaempferol, morin, myricetin, haringenin, or quercetin to human liver microsomes inhibited the hydroxylation of benzo(a)pyrene. In contrast to these results, the addition of flavone, nobiletin, tangeretin, or 7,8-benzoflavone to human liver microsomes caused a many-fold stimulation in the hydroxylation of benzo(a)pyrene, the metabolism of aflatoxin B1 to 2,3-dihydro-2,3-dihydroxyaflatoxin B1, and the metabolic activation of aflatoxin B1 to mutagenic products. Quercetin, morin, and kaempferol inhibited cytochrome c (P-450) reductase in human liver microsomes whereas flavone and 7,8-benzoflavone had no effect. These results suggest that the inhibitory effects of quercetin, morin, and kaempferol on monooxygenase activity may be caused at least in part by an inhibition in the reduction of cytochrome P-450. An examination of the structural features required for the inhibition and stimulation of benzo(a)pyrene hydroxylation indicated that all of the 12 flavonoid inhibitors that were studied possessed hydroxyl groups whereas the flavonoid activators were less polar molecules that lacked hydroxyl groups.
Cancer Res 1981 Jan
PMID:Activation and inhibition of benzo(a)pyrene and aflatoxin B1 metabolism in human liver microsomes by naturally occurring flavonoids. 744 77

DT-diaphorase (DTD) is an important enzyme for the bioreductive activation of the new alkylating indoloquinone EO9. In preclinical studies, EO9 has shown selective anti-tumour activity against solid tumours and under hypoxic conditions. The levels of three reductive enzymes have been determined in three types of human solid tumours, together with corresponding normal tissues and normal liver. DTD enzyme activities were measured in tumour extracts using 2,6-dichlorophenolindophenol (DCPIP) and NADH as substrates; cytochrome P450 reductase or cytochrome b5 reductase activities were assessed with cytochrome c and NADPH or NADH respectively. DTD activity was highest in non-small-cell lung (NSCLC)-tumours (mean 123 nmol DCPIP min-1 mg-1), followed by colon carcinoma (mean 75 nmol min-1 mg-1) and squamous cell carcinoma of the head and neck (6-fold lower than NSCLC). DTD activity was very low in normal liver and normal lung (4-6 nmol min-1 mg-1), while the levels in normal colon mucosa or normal mucosa of the head and neck region were in the same range as the corresponding tumours. The levels of the two other reductive enzymes, cytochrome P450 reductase (CP450R) and cytochrome b5 reductase (Cb5R), were 5 to 25-fold lower than those of DTD in all the tissues, except for normal liver, in which DTD was 2 to 4-fold lower. The degree of variation found for DTD (range 4-250 nmol min-1 mg-1), was not observed for these enzymes (CP450R, 0.8-7.8 nmol cytochrome c min-1 mg-1; Cb5R, 3.5-27.6 nmol min-1 mg-1).(ABSTRACT TRUNCATED AT 250 WORDS)
Br J Cancer 1995 Oct
PMID:DT-diaphorase activity in normal and neoplastic human tissues; an indicator for sensitivity to bioreductive agents? 754 40

We have established a system in which a human cell line generated reactive oxygen species (ROS), using a dimethyl sulfoxide-differentiated promyelocytic leukemia cell line HL60 (DMSO-HL60), which has characteristics similar to those of human neutrophils. DMSO-HL60 generated O2- upon stimulation with a tumor promoter, phorbol myristate acetate (PMA). O2- generation, determined as O2- release from the PMA-stimulated cells by the reduction of cytochrome c, was dependent on the dose of PMA and reached almost maximal with 2.0 nM PMA. PMA dose-dependently increased 8-hydroxydeoxyguanosine (8OHdG) in DMSO-HL60, typical of mutagenic oxidative DNA damage. The 8OHdG level, determined by electrochemical detection with high performance liquid chromatography, also became almost maximal with 2.0 nM PMA. The amount of O2- generation and that of the 8OHdG induction by PMA in human neutrophils were similar to those in DMSO-HL60. Superoxide dismutase inhibited the 8OHdG induction by about 60%, whereas catalase, deferoxamine, or thiols inhibited it almost completely. Dilution of PMA-stimulated DMSO-HL60 decreased the concentration of ROS releasing to the media from the cells. However, it did not decrease the ROS generation per cell or the 8OHdG induction. The addition of H2O2 to unstimulated DMSO-HL60 did not increase the 8OHdG level. These findings indicate that DMSO-HL60 could be used as a substitute for human neutrophils, that the concentration of ROS is not the only determinant for the 8OHdG induction, but that it requires both acquisition of susceptibility to ROS by reduction of iron by O2- and formation of H2O2, and that ROS increase 8OHdG by attacking the ROS-generating cell.
Cancer Res 1994 Nov 15
PMID:Establishment of a human system that generates O2- and induces 8-hydroxydeoxyguanosine, typical of oxidative DNA damage, by a tumor promotor. 795 11

Monocyte and macrophage dysfunction may be important for both immunopathogenesis and clinical manifestations in subgroups of patients with primary hypogammaglobulinaemia. In the present study we examined the ability to generate reactive oxygen species (ROS) in isolated monocytes from these patients by two different methods: superoxide dismutase (SOD) inhibitable cytochrome c reduction by O2- and nitroblue tetrazolium (NBT) reduction. Monocyte from patients with common variable immunodeficiency (CVI) demonstrated significantly enhanced ROS generation both unstimulated and stimulated (unopsonized zymosan and phorbol myristate acetate (PMA)). The enhanced oxidative burst response in CVI patients was found both with and without serum containing medium. Furthermore, serum from CVI patients did significantly enhance the oxidative burst response in monocytes from healthy blood donors compared with the effect of control serum. The enhanced ROS generation in CVI patients was significantly correlated with elevated serum levels of neopterin, reduced numbers of CD4+ lymphocytes in peripheral blood and occurrence of splenomegaly. In contrast to the CVI group, monocytes from patients with X-linked agammaglobulinaemia (XLA) did not show enhanced ROS generation. The increased oxidative burst response in monocytes from CVI patients most probably reflects in vivo activation of these cells. Our observations indicate the presence of a subgroup of CVI patients characterized by chronic immune activation particularly of monocytes. The enhanced ROS generation might be involved in immunopathogenesis (e.g. T cell dysfunction) and in the pathogenesis of clinical manifestations (e.g. malignancies and autoimmune disorders) in these patients.
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PMID:Enhanced generation of reactive oxygen species in monocytes from patients with common variable immunodeficiency. 805 Jan 70

More than 60 mouse monoclonal antibodies directed to cytochrome c from Candida krusei with different specificities were raised. Most of these monoclonal antibodies, except for three of them, did not cross-react with bovine cytochrome c. By the immunoblotting method, the monoclonal antibodies of clones HCC 5-13, 9-2, and 10-5 reacted with the Candida cytochrome c, which had been transferred onto nitrocellulose membrane, but those of clones HCC 1-22, 6-3, and 17-3 did not, although all these monoclonal antibodies strongly reacted with coated Candida cytochrome c on plastic immunoplates when examined by ELISA. On the contrary, monoclonal antibody activities of clones HCC 1-22, 6-3, and 17-3 in binding to the coated cytochrome c in ELISA were inhibited competitively by the addition of extra Candida cytochrome c, whereas those of clones HCC 5-13, 9-2, and 10-5 were not inhibited. Among these monoclonal antibodies, the antibody of clone HCC 6-3, which showed a good reactivity to added cytochrome c in inhibiting ELISA reaction but was not reactive with the transblotted cytochrome c on nitrocellulose, was found to be reactive with human lung cancer tissues specifically with no reactivity to normal tissues. The immunostaining of lung cancer tissue showed that this mouse monoclonal antibody to Candida cytochrome c reacted to the cytoplasmic fraction of the cancer cells specifically.
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PMID:Cancer-specific binding of a mouse MAb vs. Candida krusei cytochrome c: an antigen recognized by a cancer-associated human MAb HB4C5. 825 72

As part of an 'enzyme-directed' approach to bioreductive drug development, we have measured the activity of NADH: cytochrome b5 reductase (B5R) in human cancer cell lines in order to assess the role of this enzyme in activating bioreductive drugs, and thus in influencing the cytotoxicity of these compounds. At present, there is no validated assay reported in the literature for measuring the activity of B5R in tumour cells, and current measurements have assumed that the enzyme activity can be measured either as the NADH-dependent reduction of cytochrome c or as the non-dicoumarol-inhibitable activity in the DT-diaphorase assay. Using p-hydroxymercuribenzoate (pHMB) as an inhibitor of B5R, we have quantified the contribution of B5R to the NADH-dependent reduction of cytochrome c and to the overall reduction of cytochrome c in the DT-diaphorase assay. In the former we found that residual uninhibited activity remained in the presence of pHMB, in some cases accounting for up to 60% of the total reduction of cytochrome c. Thus, simply measuring the NADH-dependent reduction of cytochrome c consistently overestimated B5R activity. We also found that the non-dicoumarol-inhibitable activity in the DT-diaphorase assay underestimated B5R activity, especially in cell lines with high DT-diaphorase activity. Therefore, we have developed a spectrophotometric assay for measuring B5R activity as the pHMB-inhibitable NADH-dependent reduction of cytochrome c. This has been used to measure the B5R activity of a panel of 22 human tumour cell lines, in which we found 7-fold and 3-fold variations in activity expressed per cell or per mg protein respectively.
Br J Cancer 1996 Oct
PMID:Development and validation of a spectrophotometric assay for measuring the activity of NADH: cytochrome b5 reductase in human tumour cells. 888 3

Supplementation of selenium in the form of selenomethionine (8 ppm) in drinking water daily has been found to be highly effective in reducing cancer incidence in male Sprague-Dawley rats fed 2-acetylaminofluorine (2-AAF) (0.05%) in the basal diet daily for 16 weeks. Selenomethionine treatment before initiation, during initiation or during the selection/promotion phases of hepatocarcinogenesis has been found to be effective in elevating hepatic microsomal cytochrome b5, cytochrome P-450 contents, triphosphopyridine nucleotide-cytochrome c-reductase and cytosolic aryl hydrocarbon hydroxylase activities to a statistically significant level measured either in the hyperplastic nodules or in the non-nodular surrounding liver parenchyma compared with 2-AAF control rats. Moreover, selenomethionine treatment throughout the study also decreased the cytosolic 1-chloro-2,4-dinitrobenzene conjugated glutathione-S-transferase and microsomal UDP-glucuronyl transferase activities to a significant level when compared with 2-AAF control rats. Furthermore, direct correlations between hyperplastic nodules and non-nodular liver areas were observed with the hepatic selenium content and also with the rates and patterns of hepatic drug metabolism. Selenomethionine was also found to protect and improve the histopathological indices without any toxic side effects as revealed from the haematoxylin and eosin staining. Our results establish the fact that selenium is particularly protective in limiting the action of 2-AAF during the initiation phase of hepatocarcinogenesis.
Eur J Cancer Prev 1996 Dec
PMID:Biochemical basis of selenomethionine-mediated inhibition during 2-acetylaminofluorene-induced hepatocarcinogenesis in the rat. 906 Dec 76

Zinc(II) phthalocyanine (ZnPC) is a new photosensitizer currently undergoing phase I and II clinical trials at Lausanne's CHUV hospital for the photodynamic therapy (PDT) of early cancer in the upper aerodigestive tract. Activated oxygen species other than singlet oxygen produced during the photosensitization of ZnPC in liposomes have been examined by electron paramagnetic resonance (EPR) spin trapping and by the cytochrome c reduction method. Visible light irradiation of ZnPC associated with liposomes in the presence of the spin trap 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) gives an EPR spectrum characteristic of the DMPO-hydroperoxyl radical spin adduct (DMPO-.OOH). Superoxide anion attains a level of 1 microM min-1 20 min after the start of irradiation as determined by the superoxide dismutase (SOD)-inhibitable reduction of cytochrome c. The yield of O2.- is strongly enhanced by physiological electron donors. An EPR spectrum characteristic of the DMPO-hydroxyl radical spin adduct (DMPO-.OH) is also observed. The addition of dimethyl sulphoxide or ethanol produces additional hyperfine splittings due to the respective hydroxyalkyl radical products, indicating the presence of free .OH. DMPO-.OH is significantly inhibited by desferrioxamine or catalase. Conversely, this adduct is enhanced by hydrogen peroxide. These data demonstrate the ability of ZnPC in liposomes to photoreact effectively by an electron transfer mechanism. Such type I processes may add to the effects of singlet oxygen in ZnPC-mediated PDT.
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PMID:Production of the free radicals O2.- and .OH by irradiation of the photosensitizer zinc(II) phthalocyanine. 920 81

High-dose Ara-C (HIDAC) induces the cleavage and activity of caspase-3 (CPP32beta/Yama/apopain), resulting in the morphological and biochemical features of apoptosis. High levels of the antiapoptotic Bcl-x(L) or Bcl-2, relative to the proapoptotic Bax, have been shown to inhibit HIDAC-induced cleavage and activity of caspase-3 and apoptosis of the human acute myeloid leukemia HL-60 cells. In a previous report, we demonstrated this inhibition, using the control HL-60 (HL-60/neo) cells and their counterparts, HL-60/Bcl-x(L), which have enforced overexpression of Bcl-x(L) and a significantly lower ratio of free to bound Bax. Results of the present studies demonstrate that, in the initiation phase of apoptosis of HL-60/neo cells due to HIDAC (10 or 100 microM for 4 h), cytochrome c is released from the mitochondria to the cytosol, followed by the loss of mitochondrial membrane potential (deltapsi m) and an increase in the reactive oxygen species; these events precede and trigger the cleavage and activity of caspase-3. These HIDAC-induced early mitochondrial and cytosolic perturbations, which represent the initiation phase of HIDAC-induced apoptosis, were inhibited in HL-60/Bcl-x(L) cells. HIDAC treatment for 4 h also modestly increased the intracellular levels of free Bax relative to Bax bound to Bcl-2 and Bcl-x(L) in HL-60/neo but not in HL-60/Bcl-x(L) cells. In HL-60/neo cells, HIDAC-induced progressive accumulation of cytochrome c in the cytosol, the decrease in deltapsi m, and the increase in reactive oxygen species were not inhibited by coculture with the tetrapeptide inhibitors of caspases that have been previously shown to inhibit Ara-C-induced cleavage and activity of caspase-3 and apoptosis. These findings indicate that Bcl-x(L) inhibits HIDAC-induced preapoptotic mitochondrial perturbations, which prevent the accumulation of cytochrome c in the cytosol, thereby preserving caspase-3 in the inactive zymogen state and checking the molecular cascade of apoptosis.
Cancer Res 1997 Aug 01
PMID:Overexpression of Bcl-X(L) inhibits Ara-C-induced mitochondrial loss of cytochrome c and other perturbations that activate the molecular cascade of apoptosis. 924 35

Green tea and black tea inhibit colon carcinogenesis in rats exposed to the cooked meat mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). In the present investigation, green tea, black tea and (-)-epigallocatechin gallate (EGCG) were shown to block the production of oxygen free radicals derived from IQ in the presence of NADPH-cytochrome P450 reductase. In kinetic studies using IQ as the substrate and DMPO as a free radical spin trap, EGCG increased the K(m) of the reaction without altering Vmax, suggesting competitive enzyme inhibition (Ki = 9.96 microM). This was confirmed in spectrophotometric studies using cytochrome c as the substrate, in which EGCG acted as a competitive inhibitor of NADPH-cytochrome P450 reductase (Ki = 9.7 microM). These results suggest that the inhibitory activities of green tea and black tea in electron spin resonance assays using IQ as the substrate for the reductase are related to an indirect effect on the enzyme rather than via direct scavenging of the free radicals. The possible implications of these findings are discussed in the context of pathways involved in the activation and detoxification of IQ in the colon.
Jpn J Cancer Res 1997 Jun
PMID:Inhibitory activity of green and black tea in a free radical-generating system using 2-amino-3-methylimidazo[4,5-f]quinoline as substrate. 926 32


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