Isolation and studies of the mutagenic activity in the Ames test of flavonoids naturally occurring in medical herbs

Hanna, Calvin; Tudek, Barbara; Kusztelak, Joanna; Szymczyk, T; Dobrowolska, B.; Glinkowska, G.; Malinowski, Jacek; Strzelecka, H

doi:10.1016/0165-1218(90)90060-f

Cited by 148 publications

(98 citation statements)

References 9 publications

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“…The findings presented here need to be interpreded side-by side with some other results, which may allow a tentative comparison of their pharmacological profile. Both apigenin and tricin lack mutagenic properties, as reflected by a variety of tests [17,18]. Their ability to inhibit cancer cell growth has been …”

Section: Discussionmentioning

confidence: 99%

Tissue distribution in mice and metabolism in murine and human liver of apigenin and tricin, flavones with putative cancer chemopreventive properties

Cai

Boocock

Steward

et al. 2006

Cancer Chemother Pharmacol

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Purpose: The flavones apigenin and tricin, which occur in leafy vegetables and rice bran, respectively, possess cancer chemopreventive properties in preclinical rodent models. Their pharmacology is only poorly understood. We compared their tissue levels in mice in vivo and their metabolism in liver fractions in vitro. Methods: Mice received apigenin or tricin (0.2%) with their diet for 5-7 days, and flavone levels were compared in the plasma, liver and gastrointestinal mucosa using HPLC-UV. Flavone metabolism was investigated in murine and human liver microsomes or cytosol in vitro co-incubated with uridine 5'-diphosphoglucuronic acid or 3'-phosphoadenosine-5' phosphosulfate. Flavone metabolites were characterized by on-line HPLCmass spectrometry. Results: After dietary administration of flavones for 7 days, levels of tricin in plasma, liver and mucosa exceeded those of apigenin by 350, 33 and 100 %, respectively.Apigenin was more rapidly glucuronidated than tricin in liver microsomes, whilst tricin underwent swifter sulfonation than apigenin in liver cytosol. For either flavone the rate of glucuronidation was much faster than that of sulfonation. Flavone monoglucuronides and monosulfates were identified as metabolites in microsomal and cytosolic incubations, respectively. Conclusions:When consumed with the diet in mice tricin seems to be more available than apigenin in blood and tissues. Differences in their glucuronidation may account for their differential availability. Thus tricin may have a pharmacokinetic advantage over apigenin. This type of information may help decide which flavonoids to select for clinical development.

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Section: Discussionmentioning

confidence: 99%

Tissue distribution in mice and metabolism in murine and human liver of apigenin and tricin, flavones with putative cancer chemopreventive properties

Cai

Boocock

Steward

et al. 2006

Cancer Chemother Pharmacol

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“…However, a serious toxicologic impediment of many flavonols, which militates against their development as cancer chemopreventive agents, is their mutagenicity as reflected by the Ames test. Quercetin at levels of typically 20 μg or more per plate (24)(25)(26) and, to a lesser extent, fisetin at ∼500 μg per plate (27), were shown to be mutagenic. There is also limited evidence for the carcinogenicity of quercetin in animals (28,29).…”

Section: Introductionmentioning

confidence: 99%

“…These toxicologic properties of quercetin militate against its further clinical development. Toxicophoric structural features considered responsible for the mutagenic potential of flavonols include phenolic hydroxy moieties in the A and B rings of the molecular scaffold (24,26,27).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Colorectal Cancer Chemopreventive Efficacy and p53-Modulating Activity of 3′,4′,5′-Trimethoxyflavonol, a Quercetin Analogue

Howells

Britton

Mazzoletti

et al. 2010

Cancer Prevention Research

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Some naturally occurring flavonols, exemplified by quercetin, seem to possess experimental cancer chemopreventive efficacy. Modulation of p53 is a mechanism thought to contribute to their activity. The hypothesis was tested that a synthetic flavonol, 3′,4′,5′-trimethoxyflavonol (TMFol), can interfere with tumor development and p53 expression in two models of colorectal carcinogenesis, Apc Min mice and human-derived HCT116 adenocarcinoma-bearing nude mice. Mice received TMFol with their diet (0.2%) from weaning to week 16 in the case of Apc Min or from either day 7 before ("TMFol early") or day 7 after ("TMFol late") tumor inoculation in HCT116 mice. The ability of TMFol to affect tumor proliferation or apoptosis, as reflected by staining for Ki-67 or cleaved caspase-3, respectively, was studied in HCT116 tumors. TMFol tumor levels were measured by high-performance liquid chromatography. Consumption of TMFol reduced small intestinal adenoma burden in Apc Min mice by 47%, compared with control mice (P < 0.002). The TMFol early regimen approximately halved HCT116 tumor size (P < 0.05), decreased tumor proliferation, and increased apoptosis, whereas the TMFol late regimen had no significant effect when compared with controls. In tumor tissues from mice, in which TMFol reduced tumor development, p53 expression was increased 3-fold in Apc Min and 1.5-fold in HCT116 tumor-bearing mice (P = 0.02). TMFol increased p53 also in cells derived from these tumors. TMFol was detected in HCT116 tumors, but levels did not correlate with tumor burden. TMFol was not mutagenic in the Ames test. The results suggest that chemical modification of the flavonol structure may generate safe and efficacious cancer chemopreventive agents. Cancer Prev Res; 3(8); 929-39. ©2010 AACR.

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“…10) Both chrysin and apigenin were found to be potent inhibitors of enzyme aromatase and can protect against breast cancer [11][12][13] and were not mutagenic in the Ames test. [14][15][16] Previous mammalian metabolic studies of chrysin and apigenin in rat showed that they are conjugated at the C-7 hydroxyl group to produce ethereal sulfates and glucuronides, although no structures were provided, and that chrysin is hydroxylated to apigenin. 17) Luteolin and apigenin were also obtained from incubation of apigenin and chrysin, respectively with rat liver microsomes.…”

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Biotransformation of Chrysin and Apigenin by Cunninghamella elegans

Ibrahim

2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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In a previous publication, the sulfation of the hydroxyl group at C-7 of naringenin by the filamentous fungus Cunninghamella elegans was reported. 1) Metabolism of quercetin with this organism produced quercetin-4Ј-sulfate. The same results were obtained with flavanones, methoxylated at C-7. 2) Preliminary studies of flavones such as kaempferol and morin as well as the flavanones hesperitin and dihydroquercetin showed that they were converted to polar metabolites by this fungus, which were hydrolyzed by mild acid at room temperature to the respective substrates. The potential of flavonoid sulfates as therapeutically useful agents, 3,4) as standards to study flavonoid conjugation by mammals, 5) and for comparison with natural products 6) requires the preparation of flavonoids sulfated at specific sites.Chemical synthesis usually provides mixtures of flavonoid sulfates with sulfate groups randomly allocated 6) and may be difficult to purify. Thus the use of microorganisms to introduce sufalte groups at specific positions of the flavonoid nucleus seems interesting. Many microbial enzymes were found to possess broad substrate specificity, yet they catalyze reactions with high degree of regio and stereospecificity. 7) In order to check the breadth of substrate specificity of C. elegans sulfating enzyme(s), two biologically active flavones: chrysin (5,7-dihydoxyflavone) and apigenin (5,7,4Ј-trihydroxyflavone) were subjected to metabolic studies using a culture of the same microorganism. Apigenin was found to possess anticarcinogenic, 8) anti-tumor promoter, 9) antioxidative, free radical scavenging and anti-inflammatory activities. 10) Both chrysin and apigenin were found to be potent inhibitors of enzyme aromatase and can protect against breast cancer 11-13) and were not mutagenic in the Ames test. [14][15][16] Previous mammalian metabolic studies of chrysin and apigenin in rat showed that they are conjugated at the C-7 hydroxyl group to produce ethereal sulfates and glucuronides, although no structures were provided, and that chrysin is hydroxylated to apigenin. 17) Luteolin and apigenin were also obtained from incubation of apigenin and chrysin, respectively with rat liver microsomes. 18) Only glucuronide and sulfate conjugates of apigenin were obtained from incubation with HepG 2 cells, which emphasizes the importance of phase II conjugation reactions in the metabolism of flavonoids. 19) Fungi are eukaryotic organisms possessing similar metabolic machinery to those of mammals and the outcome of xenobiotic metabolism in both systems is expected to be closely related. 20) Since microorganisms are known to hydroxylate flavonoids at the C-4Ј position, 21) an additional goal of this work was to convert chrysin to the far more expensive and important apigenin. No microbial biotransformation studies on chrysin or apigenin have previously been reported. Results and DiscussionMicrobial transformation studies, using C. elegans, have indicated the capability of this microorganism to simulate metabolic reactions of drugs perf...

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Isolation and studies of the mutagenic activity in the Ames test of flavonoids naturally occurring in medical herbs

Cited by 148 publications

References 9 publications

Tissue distribution in mice and metabolism in murine and human liver of apigenin and tricin, flavones with putative cancer chemopreventive properties

Tissue distribution in mice and metabolism in murine and human liver of apigenin and tricin, flavones with putative cancer chemopreventive properties

Preclinical Colorectal Cancer Chemopreventive Efficacy and p53-Modulating Activity of 3′,4′,5′-Trimethoxyflavonol, a Quercetin Analogue

Biotransformation of Chrysin and Apigenin by Cunninghamella elegans

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