Effect of ellagic acid and hydroxylated flavonoids on the tumorigenicity of benzo[a]pyrene and (±)-7β, 8α-dihydroxy-9α, 10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene on mouse skin and in the newborn mouse

Chang, Richard L.; Huang, Mou‐Tuan; Wood, Alexander W.; Wong, Ching-Quo; Newmark, Harold L.; Yagi, Haruhiko; Sayer, Jane M.; Jerina, Donald M.; Conney, Allan H.

doi:10.1093/carcin/6.8.1127

Cited by 105 publications

(28 citation statements)

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“…The observation that a dietary supplement of Q inhibits the development of 7,12-dimethylbenzanthracene and N-nitrosomethylurea induced rat mammary cancer (Verma et al, 1988) strongly support the possibility that Q could also be active in vivo. In addition Q and certain related flavonoids may be inhibitors of experimental skin carcinogenesis (Nakadate et al, 1984;Nishino et al, 1984;Chang et al, 1985). Although the mechanism of the antiproliferative activity of Q remains to be clarified, our data suggest that as in human breast cancer (Markaverich et al, 1988) and leukaemic cells (Larocca et al, 1990), this flavonoid may regulate cell growth through a binding interaction with type II EBS.…”

Section: Nm)mentioning

confidence: 68%

Inhibitory effect of quercetin on OVCA 433 cells and presence of type II oestrogen binding sites in primary ovarian tumours and cultured cells

Scambia

Ranelletti²,

Panici³

et al. 1990

Br J Cancer

129

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Summary We investigated the effect of the flavonoid quercetin (Q) on the proliferation of the ovarian cancer cell line OVCA 433. Growth experiments demonstrated that Q exerted a reversible dose-dependent inhibition of cell proliferation in the range of concentrations between 10 nm and 10 M. Two other flavonoids tested, rutin and hesperidin, were ineffective in inhibiting cell growth. Cell cycle analysis showed that the growth inhibitory effect of Q was due to a blocking effect in the GO/GI phase. Using a whole cell assay with (6,7-3H) (Gabor, 1988). Recently it has been reported that in the rat uterus and in the MCF-7 human breast cancer cell line the flavonoid quercetin (Q) inhibits cell growth and the uterotrophic response to oestradiol (Markaverich et al., 1988 Growth experiments Cells were plated in six-well flat bottom plates (Falcon 3046, Becton Dickinson, Lincoln Park, NJ, USA) at a concentration of I x 105 cells ml-' in MEM supplemented as above. After 24 h, the medium was replaced with fresh medium and Q (3,3',4',5,7-pentahydroxyflavone), rutin (3-rhamnosylglucoside of Q) and hesperidin (7-rhamnosylglucoside of Hesperitin) (3'-5-3-hydroxy-4-methoxy-flavanone) (Aldrich, Steinhein, FRG) were added from an absolute ethanol (Q) or DMSO stock solution (rutin, hesperidin). Control cells were treated with the same amount of vehicle alone. The final ethanol and DMSO concentration never exceeded 1 % (v/v) and 0.5% (v/v), in either control or treated samples, respectively.Quadruplicate haemocytometer counts of triplicate culture dishes were performed at the time indicated in the figures.Cell cycle analysis OVCA 433 cells were plated at a concentration of I x 105 cells ml-' in MEM supplemented as above. Twenty-four hours after plating, medium was replaced with fresh medium containing 1O0M Q or vehicle alone (ethanol). After 3 days, cells were incubated for 30 min at 37°C in the same medium with 10ftM bromodeoxyuridine (Sigma Deisenhofen, FRG

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Section: Nm)mentioning

confidence: 68%

Inhibitory effect of quercetin on OVCA 433 cells and presence of type II oestrogen binding sites in primary ovarian tumours and cultured cells

Scambia

Ranelletti²,

Panici³

et al. 1990

Br J Cancer

129

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“…These mechanisms include spontaneous hydrolysis to tetrols and keto diols, non-enzymatic as well as enzymatic metabolism to triols and triol epoxides, hydration by epoxide hydrolase (EH) and glutathione (GSH) S-transferase (GST)-catalyzed conjugation with GSH (12)(13)(14)(15)(16)(17). In addition, certain plant phenols, such as ellagic acid, have been shown to inhibit mutagenic and carcinogenic effects of anti-BaPDE through direct interaction with this diol epoxide (18,19). Since BaPDE is a poor substrate for EH (20), the most important mechanism of BaPDE inactivation seems to be its conjugation with GSH.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of inhibition of benzo[a]pyrene-induced forestomach cancer in mice by dietary curcumin

et al. 1998

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Curcumin (diferuloylmethane), the major yellow pigment in turmeric, has been shown to inhibit benzo[a]pyrene (BaP)-induced forestomach cancer in mice through mechanism(s) not fully understood. It is well known that while cytochrome P4501A1 (CYP1A1) and epoxide hydrolase (EH) are important in the conversion of BaP to its activated form, (⍣)-anti-7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(⍣)-anti-BaPDE], the detoxification of (⍣)-anti-BaPDE is accomplished by glutathione (GSH) S-transferases (GST). Therefore, it seems reasonable to postulate that curcumin may exert anti-carcinogenic activity either by inhibiting activation of BaP or (and) by enhancing the detoxification of (⍣)-anti-BaPDE. Administration p.o. of 2% curcumin in the diet to female A/J mice for 14 days, which has been shown to cause a significant inhibition in BaP-induced forestomach tumorigenesis, resulted in a modest but statistically significant reduction in hepatic ethoxyresorufin O-deethylase (EROD) activity, a reaction preferentially catalyzed by CYP1A1. While EROD activity could not be detected in the forestomach of either control or treated mice, curcumin feeding caused a statistically significant increase (~2.3-fold) in hepatic EH and GST activities. Hepatic and forestomach GSH levels, and forestomach EH and GST activities were not affected by curcumin treatment. Even though the levels of various hepatic GST isoenzymes were significantly increased upon curcumin feeding, maximum induction was noticed for the pi class isoenzyme (mGSTP1-1), which among murine hepatic GSTs is highly efficient in the detoxification of (⍣)-anti-BaPDE. In conclusion, the results of the present study suggest that curcumin may inhibit BaP-induced forestomach cancer in mice by affecting both activation as well as inactivation pathways of BaP metabolism in the liver.

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“…Ellagic acid (2,3,7,8-tetrahydroxy [J]benzopyrano [5,4,3-cde][J]benzopyran-5,10-dione), a natural product shikimate derivative present in soft fruits and vegetables (1-3), inhibits the carcinogenicity of benzo[a]pyrene (B[a]P) (4) and the carcinogenicity and mutagenicity (5)(6)(7)(8) and DNA binding (9,10) of benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), an activated form of B[a]P. It was suggested that the chemopreventive activity of ellagic acid results from its ability to accelerate the detoxification of BPDE by forming a BPDE-ellagic acid adduct (11). It was further suggested that the reason for the rapid reaction between BPDE and ellagic acid resulted from an initial ir-7r nonbonded interaction.…”

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confidence: 99%

Inhibition of N-methyl-N-nitrosourea-induced mutagenicity and DNA methylation by ellagic acid.

Dixit¹,

Gold²

1986

Proc. Natl. Acad. Sci. U.S.A.

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Ellagic acid, a naturally occurring plant phenol, inhibits the activity of the direct-acting mutagen N-methyl-N-nitrosourea (MeNU) in Salmonella typhimurium TA100.Ellagic acid at 0.10, 0.25, 0.50, and 1.00 mM inhibited the mutagenicity of MeNU (0.40 mM) by 3%, 13%, 45%, and 60%, respectively. Ellagic acid (3 mM) also inhibited the mutagenic activity of in the presence of pyrazole-induced rat liver fraction S-9. The effect of ellagic acid on DNA methylation was studied by incubating 0, 0.72, 1.32, 2.64, and 6.60 mM ellagic acid with DNA (0.9 mM nucleotide) and PHJMeNU (0.66 mM). HPLC analysis of DNA hydrolysates showed that ellagic acid caused a dose-dependent 36-84% decrease in 06-methylguanine but only a 20% decrease in the 7-methylguanine adduct. Under conditions where methylation at the 06 position of guanine in double-stranded DNA was inhibited 65% by ellagic acid, no significant inhibition of either 06-or 7-methylguanine formation was detected in single-stranded DNA. Affinity-binding studies revealed that [3H]eilagic acid binds equally to doublestranded or single-stranded DNA but that poly(dA dT) binds 1.5 times as much ellagic acid as does poly(dG-dC). The binding of ellagic acid to DNA is dependent on the concentration of both ellagic acid and DNA. The specific inhibition of 06. methylguanine formation only in double-stranded DNA and the relatively low inhibition of 7-methylguanine formation rule out the possibility that ellagic acid prevents DNA alkylation by scavenging the electrophilic intermediate generated in the hydrolysis of MeNU. The results suggest that ellagic acid inhibition of MeNU-induced mutagenicity is due to specific inhibition of methylation at the 06 position of guanine through an ellagic acid-duplex DNA afflnity-binding mechanism.Ellagic acid (2,3,7,8-tetrahydroxy[J]benzopyrano [5,4,3-cde][J]benzopyran-5,10-dione), a natural product shikimate derivative present in soft fruits and vegetables (1-3), inhibits the carcinogenicity of benzo[a]pyrene (B[a]P) (4) and the carcinogenicity and mutagenicity (5-8) and DNA binding (9, 10) of benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), an activated form of B[a]P. It was suggested that the chemopreventive activity of ellagic acid results from its ability to accelerate the detoxification of BPDE by forming a BPDE-ellagic acid adduct (11). It was further suggested that the reason for the rapid reaction between BPDE and ellagic acid resulted from an initial ir-7r nonbonded interaction. The apparent second-order rate constant for the disappearance of BPDE at pH 7.0 is more than 300-fold faster in the presence of ellagic acid (11). In summary, the proposed antimutagenic and antitumorigenic activity of ellagic acid was suggested to result from its direct interception of the "ultimate" electrophilic form of B[a]P, thereby preventing DNA adduction.While this mechanism may be effective with the reactive electrophiles generated in the metabolism of polycyclic aromatic hydrocarbons, it is not likely that such a "scavenging" mechanism would be eff...

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Effect of ellagic acid and hydroxylated flavonoids on the tumorigenicity of benzo[a]pyrene and (±)-7β, 8α-dihydroxy-9α, 10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene on mouse skin and in the newborn mouse

Cited by 105 publications

References 0 publications

Inhibitory effect of quercetin on OVCA 433 cells and presence of type II oestrogen binding sites in primary ovarian tumours and cultured cells

Inhibitory effect of quercetin on OVCA 433 cells and presence of type II oestrogen binding sites in primary ovarian tumours and cultured cells

Mechanism of inhibition of benzo[a]pyrene-induced forestomach cancer in mice by dietary curcumin

Inhibition of N-methyl-N-nitrosourea-induced mutagenicity and DNA methylation by ellagic acid.

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