Disubstituted amino‐, nitroso‐, and nitrofluorenes: A physicochemical basis for structure‐activity relationships in salmonella typhimurium

Vance, William A.; Wang, Yi Y.; Okamoto, Howard S.

doi:10.1002/em.2860090204

Cited by 40 publications

(25 citation statements)

References 65 publications

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“…Analogous studies of other groups of chemicals having a broad range of mutagenic potency in Salmonella have been reported in the following references: nitro-and aminoaromatics, Vance and Levin [1984], Vance et al, [1985Vance et al, [ , 1986Vance et al, [ , 1987; nitroarenes, Maynard et al, [1986]; and nitronaphthofurans, Arnaise et al, [ 19861.…”

Section: Introduction Historicalmentioning

confidence: 99%

Quantitative structure‐activity relationships of heterocyclic amine mutagens formed during the cooking of food

Hatch

Knize

Felton

1991

Environ and Mol Mutagen

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The major protein-rich foods, particularly muscle meats, contain part-per-billion quantities of potent mutagens formed by frying or broiling to a well-done state. Related mutagens are formed by pyrolysis of amino acids or proteins and in heated model systems. The thermic mutagens so far identified are heterocyclic aromatic amines of aminoimidazo-azaarene (AIA) and aminocarboline classes. The chemicals require activation by enzymes to form metabolites reactive with nucleic acids. These thermic mutagens, and numerous synthetic congeners, exhibit an enormous range of potency as frameshift mutagens in the Ames/Salmonella assay. However, structural variations are nominal within the two classes. Structural parameters that appeared relevant to determining potency were selected for 38 AIAs and 23 amino-carbolines. For the AIA class these were: the number of fused rings, the number of heteroatoms in Rings 2 and 3, methyl substitution on imidazo ring nitrogen atoms, and methyl substitution on ring carbon atoms. For the amino-carboline class the structural parameters were: the position of the pyridine-type nitrogen atom in Ring 1, the substitution position of the exocyclic amino group on Ring 1, and methyl substitution on ring carbon atoms. These structural parameters may influence mutagenic potency in the following ways. 1) Electronic or steric effects may determine the reactivity and stability of the ultimate mutagenic metabolite. Optimal balance of reactivity and lifetime of this transient intermediate may be required for access to and reaction with nuclear DNA to cause mutations. 2) Substitution on the rings may block detoxication reactions. The structural parameters identified should prove useful in predicting the mutagenicity of untested compounds of these types.

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Section: Introduction Historicalmentioning

confidence: 99%

Quantitative structure‐activity relationships of heterocyclic amine mutagens formed during the cooking of food

Hatch

Knize

Felton

1991

Environ and Mol Mutagen

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“…The mechanism of genotoxicity is thought to involve metabolic reduction of these nitro-PAHs, so that reduction of the nitro group is considered a key metabolic reaction in the activation of 2-nitrofluorene to mutagens (McCoy et al, 1981;Vance et al, 1987) and ultimate carcinogen (Beije and Möller, 1988). In our previous study, it was demonstrated that 2-nitrofluorene was mainly metabolized to 2-aminofluorene and its acylated metabolites in rat and dog (Ueda et al, 2001).…”

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confidence: 99%

Xanthine Oxidase-Catalyzed Metabolism of 2-Nitrofluorene, a Carcinogenic Air Pollutant, in Rat Skin

Ueda¹,

Kawa²,

Ohashi³

et al. 2003

Drug Metab Dispos

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ABSTRACT:The reductive metabolism of 2-nitrofluorene, a carcinogenic air pollutant, in rat skin microsomes and cytosol was investigated. 2-Nitrofluorene was reduced to the corresponding amine by the microsomes with NADPH and by the cytosol with 2-hydroxypyrimidine or 4-hydroxypyrimidine under anaerobic conditions. The cytosolic activity was much higher than that of skin microsomes. The 2-or 4-hydroxypyrimidine-linked nitroreductase activity was inhibited by oxypurinol and (؉/؊)-8-(3-methoxy-4-phenylsulfinylphenyl) pyrazolo[1,5-a]-1,3,5-triazine-4(1H)-one (BOF-4272), inhibitors of xanthine oxidase, but not by menadione, chlorpromazine and isovanillin, inhibitors of aldehyde oxidase. When skin cytosol was applied to a DEAE-cellulose column, the fractions containing xanthine oxidase exhibited a marked 2-hydroxypyrimidine-linked nitroreductase activity. In contrast, the aldehyde oxidase fraction showed little activity. Nitroreductase fractions obtained by ion exchange chromatography showed a band in Western blotting analysis using anti-rat xanthine oxidase. Moreover, the xanthine oxidase fraction exhibited a significant nitroreductase activity in the presence of 2-hydroxypyrimidine, 4-hydroxypyrimidine or hypoxanthine, and these activities were inhibited by inhibitors of xanthine oxidase. These results indicated that reduction of 2-nitrofluorene in the skin was mainly catalyzed by xanthine oxidase.

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“…Partially purified fractions containing xanthine oxidase activity showed immunoreactivity against anti-rat xanthine oxidase. The authors (Ueda et al 2003) conclude that in rat skin xanthine oxidase is important for the nitroreduction (at least of the substrate used, 2-nitrofluorene), a metabolic step in the activation of nitroarenes to electrophilically reactive mutagens (Vance et al 1987). …”

Section: Xenobiotica-metabolizing Enzymes In the Rat Skinmentioning

confidence: 99%

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

2018

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Studies on the metabolic fate of medical drugs, skin care products, cosmetics and other chemicals intentionally or accidently applied to the human skin have become increasingly important in order to ascertain pharmacological effectiveness and to avoid toxicities. The use of freshly excised human skin for experimental investigations meets with ethical and practical limitations. Hence information on xenobiotic-metabolizing enzymes (XME) in the experimental systems available for pertinent studies compared with native human skin has become crucial. This review collects available information of which—taken with great caution because of the still very limited data—the most salient points are: in the skin of all animal species and skin-derived in vitro systems considered in this review cytochrome P450 (CYP)-dependent monooxygenase activities (largely responsible for initiating xenobiotica metabolism in the organ which provides most of the xenobiotica metabolism of the mammalian organism, the liver) are very low to undetectable. Quite likely other oxidative enzymes [e.g. flavin monooxygenase, COX (cooxidation by prostaglandin synthase)] will turn out to be much more important for the oxidative xenobiotic metabolism in the skin. Moreover, conjugating enzyme activities such as glutathione transferases and glucuronosyltransferases are much higher than the oxidative CYP activities. Since these conjugating enzymes are predominantly detoxifying, the skin appears to be predominantly protected against CYP-generated reactive metabolites. The following recommendations for the use of experimental animal species or human skin in vitro models may tentatively be derived from the information available to date: for dermal absorption and for skin irritation esterase activity is of special importance which in pig skin, some human cell lines and reconstructed skin models appears reasonably close to native human skin. With respect to genotoxicity and sensitization reactive-metabolite-reducing XME in primary human keratinocytes and several reconstructed human skin models appear reasonably close to human skin. For a more detailed delineation and discussion of the severe limitations see the Conclusions section in the end of this review.

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Disubstituted amino‐, nitroso‐, and nitrofluorenes: A physicochemical basis for structure‐activity relationships in salmonella typhimurium

Cited by 40 publications

References 65 publications

Quantitative structure‐activity relationships of heterocyclic amine mutagens formed during the cooking of food

Quantitative structure‐activity relationships of heterocyclic amine mutagens formed during the cooking of food

Xanthine Oxidase-Catalyzed Metabolism of 2-Nitrofluorene, a Carcinogenic Air Pollutant, in Rat Skin

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

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