Ascorbic acid inhibits covalent binding of enzymatically generated 2-acetyl-aminofluorene-N-sulfate to DNA under conditions in which it increases mutagenesis in salmonella TA-1538

Andrews, Larry S.; Fysh, Jacquelene M.; Hinson, Jack; Gillette, James R.

doi:10.1016/0024-3205(79)90280-7

Cited by 18 publications

(2 citation statements)

References 12 publications

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“…TCDD can be added to the growing list of such compounds: bromobenzene (7); acetaminophen (26,57), numerous polycyclic hydrocarbons (6,30,42,45,49,50,62,63); 2-acetylaminoflu orene (1,3,38,49); aflatoxin B, (13. 64); CS2 (11); isoniazid (4,40,41); parathion (27); furosemide (71); estrogen (59); phenytoin (36); trichloroethylene (2); hexachlorophene (39); We propose that any one (or all) of three possible arene oxides of TCDD ( fig.…”

Section: Discussionmentioning

confidence: 99%

2,3,7,8-Tetrachlorodibenzo-p-Dioxin: Covalent Binding of Reactive Metabolic Intermediates Principally to Protein in vitro

Guenthner¹,

Fysh²,

Nebert³

1979

Pharmacology

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is metabolized by the mouse liver cytochrome P-450-mediated monooxygenase system to reactive intermediates which bind ‘cova-lently’ to cellular macromolecules. Although very difficult to quantitate, the presumably covalent binding to microsomal protein occurs between 120 and 2,640 times more readily than binding to deproteinized DNA in the in vitro reaction. Because of the extremely high rate of binding to protein rather than to DNA, it is visualized that TCDD metabolites may be so reactive that they bind in or near the P-450-active site where the TCDD is monooxygenated. This extreme reactivity may preclude the formation of detectable quantities of phenols, dihydrodiols, or conjugated products. The rate of TCDD metabolism is estimated to be between 9,000 and 36,000 times lower than the rate of P-450-mediated benzo[a]pyrene metabolism. To our knowledge, this is the first demonstration that TCDD is metabolized in any organism. There remains the possibility, however unlikely, that this covalently-bound radioactivity represents metabolites of contaminants -present in the radiolabeled TCDD sample in very minute amounts – rather than metabolites of tritiated TCDD itself. The possible relationship between P450-mediated metabolism of this environmental contaminant and its extreme toxicity or teratogenicity is discussed.

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Section: Discussionmentioning

confidence: 99%

2,3,7,8-Tetrachlorodibenzo-p-Dioxin: Covalent Binding of Reactive Metabolic Intermediates Principally to Protein in vitro

Guenthner¹,

Fysh²,

Nebert³

1979

Pharmacology

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“…On the other hand, VC and ascorbate are reported to inhibit the formation of mutagenic N-nitroso compounds from nitrite and nitrate. 13,14) Thus, VC reduces the mutagenic activity of N-methyl-N′ -nitro-N-nitrosoguanidine (MNNG) by chemically interacting with it, 15 17) as well as with 2-acetyl-amino‰uorene, 18) ethylene methanesulfonate, 19) a‰atoxin B 1 , 20) dimethylnitrosamine, and other mutagens. 21) The important physiological functions of VC are largely dependent on its unique 2,3-enediol moiety in theˆve-membered lactone ring, which exhibits strong electron-donating ability.…”

Section: Introductionmentioning

confidence: 99%

Antimutagenic Activity of a Novel Ascorbic Derivative, Disodium Isostearyl 2-O-L-Ascorbyl Phosphate

Hisama¹,

Matsuda²,

Shibayama³

et al. 2008

YAKUGAKU ZASSHI

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A novel amphiphilic vitamin C derivative, disodium isostearyl 2-O-L-ascorbyl phosphate (VCP-IS-2Na) possessing an alkyl chain of C 18 to a stable ascorbate derivative sodium L-ascorbic acid 2-phosphate (VCP-Na), was synthesized and evaluated as an anti-mutagen with suppressive eŠect on SOS-inducing activity on mutagen in the Salmonella typhimurium TA1535/pSK1002 umu test. VCP-IS-2Na was assayed with chemical mutagens, N-methyl-N′ -nitro-Nnitrosoguanidine (MNNG), 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide (furylfuramide) and 4-nitroquinolin 1-oxide (4NQO), which do not require liver metabolizing enzymes. VCP-IS-2Na at a concentration of 0.40 mmol/ml suppressed 66.2％, 54.7％ and 60.2％ of the SOS-inducing activity on MNNG, furylfuramide, and 4NQO, and the 50％ inhibitory dose value (ID 50 ) was 0.12 mmol/ml, 0.26 mmol/ml, and 0.17 mmol/ml, respectively. In addition, VCP-IS-2Na was assayed with 2-aminoanthracene (2AA) and 3-amino-1,4-dimethyl-5H-pyrido [4,3-b]indole (Trp-P-1), which require liver metabolizing enzymes. To study the structure-activity relationship, L-ascorbic acid (VC) and VCP-Na were also assayed with all mutagens. VCP-IS-2Na, suppressed the chemical and physical mutagens-induced SOS response greater than VC and VCP-Na in the umu test. Also, the antimutagenic activities of VCP-IS-2Na, VC, and VCP-Na against MNNG and Trp-P-1 were assayed by the Ames test using the S. typhimurium TA100 strain. In summary, this research suggests that VCP-IS-2Na showed potent antimutagenic eŠects against chemical mutagens and UV irradiation.

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Vitamins and Cancer

Shamberger

1984

Nutrition and Cancer

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Ascorbic acid inhibits covalent binding of enzymatically generated 2-acetyl-aminofluorene-N-sulfate to DNA under conditions in which it increases mutagenesis in salmonella TA-1538

Cited by 18 publications

References 12 publications

2,3,7,8-Tetrachlorodibenzo-<i>p</i>-Dioxin: Covalent Binding of Reactive Metabolic Intermediates Principally to Protein <i>in vitro</i>

2,3,7,8-Tetrachlorodibenzo-<i>p</i>-Dioxin: Covalent Binding of Reactive Metabolic Intermediates Principally to Protein <i>in vitro</i>

Antimutagenic Activity of a Novel Ascorbic Derivative, Disodium Isostearyl 2-<i>O</i>-L-Ascorbyl Phosphate

Vitamins and Cancer

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