Comparative mutagenesis of plant flavonoids in microbial systems

Hardigree, A.A.; Epler, J.L.

doi:10.1016/0165-1218(78)90014-9

Cited by 136 publications

(52 citation statements)

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“…Many recent studies have pointed out the importance of gut flora in transforming a wide variety of naturally occurring glycosides of mutagens to active forms (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(24)(25)(26). These studies indicate that the rat liver homogenate used in the Salmonella test at present should be complemented by the addition of microbial enzymes to the test to allow for a more complete assay of potential carcinogens in the plant world.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies indicate that many naturally occurring glycosides of mutagenic aglycones are not mutagenic in the Salmonella test (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). These glycosides are hydrolyzed by the bacteria in the human intestine where the mutagen is liberated.…”

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confidence: 99%

“…This article must therefore be hereby marked "advertisement" in accordance with 18 (15,22), also was assayed for glycosidic activities and its protein content was determined (30 (10)(11)(12)32). Fecalase showed no significant decrease in activity (<15%) when stored at -80'C for 9 months, as measured with a rutin (a rutinoside of quercetin) mutagenicity assay.…”

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confidence: 99%

“…An enormous variety of substances are present as glycosides in the plant kingdom (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). It is desirable to have an enzyme preparation for use in mutagenicity tests that will hydrolyze the hundreds of sugars in these glycosides.…”

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confidence: 99%

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Fecalase: a model for activation of dietary glycosides to mutagens by intestinal flora.

Tamura¹,

Gold²,

Ferro-Luzzi³

et al. 1980

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

133

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Many substances in the plant kingdom and in man's diet occur as glycosides. Recent studies have indicated that many glycosides that are not mutagenic in tests such as the Salmonella test become mutagenic upon hydrolysis of the glycosidic linkages. The Salmonella test utilizes a liver homogenate to approximate mammalian metabolism but does not provide a source of the enzymes present in intestinal bacterial flora that hydrolyze the wide variety of glycosides present in nature. We describe a stable cell-free extract of human feces, fecalase, which is shown to contain various glycosidases that allow the in vitro activation of many natural glycosides to mutagens in the Salmonella/liver homogenate test. Many beverages, such as red wine (but apparently not white wine) and tea, contain glycosides of the mutagen quercetin. Red wine, red grape juice, and tea were mutagenic in the test when fecalase was added, and red wine contained considerable direct mutagenic activity in the absence of fecalase. The implications of quercetin mutagenicity and carcinogenicity are discussed.Damage to DNA by environmental mutagens, both natural and man-made, is likely to be a major cause of cancer and other diseases (1, 2). The Salmonella test (3), along with other short-term tests (4), is being used to survey a wide variety of substances in our environment for mutagenicity. The test measures back mutation in several specially constructed mutants of Salmonella bacteria. A homogenate of rat liver (or other mammalian liver) is added to the (Salmonella) test as an approximation of mammalian metabolism (3). By using this system, approximately 85% 1 5% of the organic carcinogens tested have been detected as mutagens (5-9).Recent studies indicate that many naturally occurring glycosides of mutagenic aglycones are not mutagenic in the Salmonella test (10-23). These glycosides are hydrolyzed by the bacteria in the human intestine where the mutagen is liberated. They are not cleaved by the liver or by liver homogenates used in the Salmonella test. For example, cycasin, a f3-D-glucoside of the mutagen methylazoxymethanol, is not mutagenic in the Salmonella test unless 3-glucosidase is added to the standard test (20,21). Cycasin is a carcinogen in rats but is not a carcinogen when tested with germ-free rats (24, 25), which lack the microorganisms that cleave the sugar from the mutagenic moiety.An enormous variety of substances are present as glycosides in the plant kingdom (10-27). It is desirable to have an enzyme preparation for use in mutagenicity tests that will hydrolyze the hundreds of sugars in these glycosides. have developed a cell-free extract of rat cecal bacteria, cecalase, for use in mutagenicity testing. 22) have used hesperidinase, a mold enzyme preparation, for this pur-The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S.

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Section: Discussionmentioning

confidence: 99%

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Fecalase: a model for activation of dietary glycosides to mutagens by intestinal flora.

Tamura¹,

Gold²,

Ferro-Luzzi³

et al. 1980

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

133

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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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