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51.
52.
Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables, such as broccoli and broccoli sprouts. This anticarcinogen was first identified as a potent inducer of Phase 2 detoxification enzymes, but evidence is mounting that SFN also acts through epigenetic mechanisms. SFN has been shown to inhibit histone deacetylase (HDAC) activity in human colon and prostate cancer lines, with an increase in global and local histone acetylation status, such as on the promoter regions of P21 and bax genes. SFN also inhibited the growth of prostate cancer xenografts and spontaneous intestinal polyps in mouse models, with evidence for altered histone acetylation and HDAC activities in vivo. In human subjects, a single ingestion of 68 g broccoli sprouts inhibited HDAC activity in circulating peripheral blood mononuclear cells 3-6 h after consumption, with concomitant induction of histone H3 and H4 acetylation. These findings provide evidence that one mechanism of cancer chemoprevention by SFN is via epigenetic changes associated with inhibition of HDAC activity. Other dietary agents such as butyrate, biotin, lipoic acid, garlic organosulfur compounds, and metabolites of vitamin E have structural features compatible with HDAC inhibition. The ability of dietary compounds to de-repress epigenetically silenced genes in cancer cells, and to activate these genes in normal cells, has important implications for cancer prevention and therapy. In a broader context, there is growing interest in dietary HDAC inhibitors and their impact on epigenetic mechanisms affecting other chronic conditions, such as cardiovascular disease, neurodegeneration and aging. 相似文献
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54.
A T Fong H I Swanson R H Dashwood D E Williams J D Hendricks G S Bailey 《Biochemical pharmacology》1990,39(1):19-26
The induction of oxidation and conjugation enzymes, the scavenging of carcinogen electrophiles, and the inhibition of aflatoxin B1 (AFB1) activation were examined as possible mechanisms of anti-carcinogenesis by indole-3-carbinol (I3C). Liver microsomal 7-ethoxycoumarin O-deethylase and 7-ethoxyresorufin O-deethylase activities were not induced significantly in rainbow trout fed diets containing 500-2000 ppm I3C for 8 days compared to trout fed the control diet. Furthermore, no detectable changes in the specific contents of cytochrome P-450 isozymes LM2 and LM4b, as measured by Western-blotting and immunoquantitation, were found in liver microsomes following dietary I3C administration. Dietary I3C had no significant effect on liver microsomal uridine diphosphate-glucuronyl-transferase activity, measured using the substrates 1-naphthol and testosterone, or on cytosolic glutathione S-transferase activity, measured using the substrate styrene oxide. The ability of I3C or its acid reaction products (RXM; generated by the reaction of I3C with HCl) to act as scavengers for the direct alkylating agent AFB1-8,9-Cl2 was examined. Addition of I3C or RXM to in vitro incubations did not inhibit the covalent binding of AFB1-8,9-Cl2 to calf thymus DNA. Kinetic analyses of microsome-mediated binding of AFB1 to DNA in vitro indicated that RXM inhibited the metabolic activation of AFB1. RXM increased the apparent Km for the AFB1-DNA binding reaction without changing the associated Vmax; the apparent Km values at 0, 3.5, 35, and 350 microM RXM were 35, 38, 66, and 86 microM for trout liver microsomes. RXM also inhibited the activation of AFB1 by rat liver microsomes, but I3C was not an effective inhibitor against AFB1-DNA binding mediated by either rat or trout liver microsomes. The results of the present study indicate that inhibition of microsome-activated AFB1 binding to DNA by I3C products may be of significant importance in I3C inhibition of hepatocarcinogenesis in trout and other species. The inhibition of carcinogen activation by I3C is contrasted with the mechanism of anti-carcinogenesis by beta-naphthoflavone, which involves induction of xenobiotic metabolizing enzymes. 相似文献
55.
Stephen Warrillow Caleb Fisher Heath Tibballs Michael Bailey Colin McArthur Pia Lawson-Smith Bheemasenachar Prasad Matthew Anstey Bala Venkatesh Gemma Dashwood James Walsham Andrew Holt Ubbo Wiersema David Gattas Matthew Zoeller Mercedes Garcia Alvarez Rinaldo Bellomo 《Journal of gastroenterology and hepatology》2020,35(5):846-854
56.
Suzui M Ushijima T Dashwood RH Yoshimi N Sugimura T Mori H Nagao M 《Molecular carcinogenesis》1999,24(3):232-237
Recent evidence suggests that the beta-catenin gene (CTNNB1) acts as an oncogene, and some human colon tumors with an intact APC gene have activating mutations in CTNNB1. In this study, mutations in the region corresponding to N-terminal phosphorylation sites (codons 1-51) of the rat Ctnnb1 gene were investigated in 20 colon tumors associated with ulcerative colitis and induced with methylazoxymethanol acetate and 1-hydroxyanthraquinone. Ninety percent (18 of 20) of the tumors induced in male F344 rats harbored mutations, which were detected in three of four adenomas (75%) and 15 of 16 adenocarcinomas (94%). Of 18 total missense mutations, 13 (72%) were G-->A transitions at position 101, three were G-->A transitions at position 94, and two were C-->T transitions at position 122, resulting in the amino acid substitutions Gly34-->Glu, Asp32-->Asn, and Thr41-->Ile, respectively. Although there were no mutations in the Apc gene, as we previously reported in the same tumor samples, the results obtained in this study strongly implicate the Apc-beta-catenin-T-cell factor (Tcf) signaling pathway in methylazoxymethanol acetate, 1-hydroxyanthraquinone-induced colon carcinogenesis. 相似文献
57.
Xu M; Schut HA; Bjeldanes LF; Williams DE; Bailey GS; Dashwood RH 《Carcinogenesis》1997,18(11):2149-2153
Indole-3-carbinol (I3C) inhibits the formation of colonic aberrant crypt
foci and DNA adducts in rats given heterocyclic amine colon carcinogens,
such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Mechanism studies
indicate that I3C induces cytochromes P4501A1 and 1A2 (CYP1A1 and CYP1A2),
isozymes that respectively metabolize IQ via ring hydroxylation or activate
the carcinogen by N-hydroxylation. The present study examined the
dose-response for induction of CYP1A1 versus CYP1A2 by I3C, and compared
the profiles of induction with the dose- response for inhibition of IQ-DNA
adducts in the colon of the F344 rat. Dietary equivalent doses of I3C in
the range 100-1000 p.p.m. increased in a dose-related manner both
ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase
(MROD) activities in the liver and colonic mucosa, and Western blots showed
a corresponding induction of CYP1A1 and CYP1A2 proteins. However, dietary
equivalent doses of I3C in the range 10-25 p.p.m. (i) reduced hepatic EROD
and MROD activities and CYP1A protein levels compared with controls, (ii)
increased the ratio of CYP1A2 versus CYP1A1, and (iii) activated IQ to a
more potent mutagen when liver microsomes from rats given I3C were used for
metabolic activation in the Salmonella assay. Rats given a single oral dose
of I3C shortly before administering IQ (5 mg/kg body wt, p.o.) exhibited
dose-related inhibition of colonic IQ-DNA adducts in the range 25-100
p.p.m. I3C, reaching 95% inhibition at doses > or = 100 p.p.m. I3C, but
IQ-DNA adducts were elevated slightly at the lowest I3C dose as compared
with the controls. The possible significance of the low versus high dose
effects of I3C are discussed in the context of human dietary exposures to
I3C and the reported chemopreventive mechanisms of I3C in vivo.
相似文献
58.
59.
Cytochrome P4501B1 mediates induction of bone marrow cytotoxicity and preleukemia cells in mice treated with 7,12-dimethylbenz[a]anthracene 总被引:6,自引:0,他引:6
Heidel SM MacWilliams PS Baird WM Dashwood WM Buters JT Gonzalez FJ Larsen MC Czuprynski CJ Jefcoate CR 《Cancer research》2000,60(13):3454-3460
Humans are exposed to polycyclic aromatic hydrocarbons (PAHs) through many environmental pollutants, especially cigarette smoke. These chemicals cause a variety of tumors and immunotoxic effects, as a consequence of bioactivation by P-450 cytochromes to dihydrodiol epoxides. The recently identified cytochrome P4501B1 (CYP1B1) bioactivates PAHs but is also a physiological regulator, as evidenced by linkage of CYP1B1 deficiency to congenital human glaucoma. This investigation demonstrates that CYP1B1 null mice are almost completely protected from the acute bone marrow cytotoxic and preleukemic effects of the prototypic PAH 7,12-dimethylbenz[a]anthracene (DMBA). CYP1B1 null mice did not produce the appreciable amounts of bone marrow DMBA dihydrodiol epoxide DNA adducts present in wild-type mice, despite comparable hepatic inductions of the prominent PAH-metabolizing P-450 cytochrome, CYP1A1. Wild-type mice constitutively expressed low levels of bone marrow CYP1B1. These findings suggest that CYP1B1 is responsible for the formation of DMBA dihydrodiol epoxides in the bone marrow. Furthermore, this study substantiates the importance of DMBA dihydrodiol epoxide generation at the site of cancer initiation and suggests that tissue-specific constitutive CYP1B1 expression may contribute to cancer susceptibility in the human population. 相似文献
60.
Sulforaphane inhibits histone deacetylase activity in BPH-1, LnCaP and PC-3 prostate epithelial cells 总被引:3,自引:0,他引:3
Sulforaphane (SFN), an isothiocyanate first isolated from broccoli, exhibits chemopreventive properties in prostate cancer cells through mechanisms that are poorly understood. We recently reported on a novel mechanism of chemoprotection by SFN in human colon cancer cells, namely the inhibition of histone deacetylase (HDAC). Here, we show that addition of 15 microM SFN also inhibited HDAC activity by 40, 30 and 40% in BPH-1, LnCaP and PC-3 prostate epithelial cells, respectively. The inhibition of HDAC was accompanied by a 50-100% increase in acetylated histones in all three prostate cell lines, and in BPH-1 cells treated with SFN there was enhanced interaction of acetylated histone H4 with the promoter region of the P21 gene and the bax gene. A corresponding 1.5- to 2-fold increase was seen for p21Cip1/Waf1 and Bax protein expression, consistent with previous studies using HDAC inhibitors, such as trichostatin A. The downstream events included cell cycle arrest and activation of apoptosis, as evidenced by changes in cell cycle kinetics and induction of multi-caspase activity. These findings provide new insight into the mechanisms of SFN action in benign prostate hyperplasia, androgen-dependent prostate cancer and androgen-independent prostate cancer cells, and they suggest a novel approach to chemoprotection and chemotherapy of prostate cancer through the inhibition of HDAC. 相似文献