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F T Hatch

Publications and source records attributed to F T Hatch.

At least 19 recordsLinked to original sources
PubMed2000

Quantitative structure-activity relationship of flavonoids for inhibition of heterocyclic amine mutagenicity.

The mutagenic/carcinogenic heterocyclic amines formed during the cooking of protein foods have been determined to be a potential risk to human health. Therefore, mitigation measures are beginning to be studied. A recent finding is that the induction of mutation in Salmonella by these amines can be inhibited by the addition of flavonoids to the assay. This study combines data on the inhibitory process with structural, ab initio quantum chemical, hydropathic, and antioxidant factors to develop a quantitative structure-activity relationship (QSAR) database and statistical analysis. For 39 diverse flavonoids the inhibitory potency varied approximately 100-fold. Three predictive variables, in order of decreasing contribution to variance, are: (1) a large dipole moment; (2) after geometric minimization of energy, a small departure from planarity (i.e., small dihedral angle between the benzopyran nucleus and the attached phenyl ring), and a low rotational energy barrier to achieving planarity; and (3) fewer hydroxyl groups on the phenyl ring. However, these variables account for less than half of the variance in inhibitory potency of the flavonoids. Frontier orbital energies and antioxidant or radical scavenging properties showed little or no relationship to potency. We conclude that interference by the flavonoids with cytochrome P450 activation of the promutagens is the probable mechanism for inhibition of mutagenesis, and suggest avenues for further research. Environ. Mol. Mutagen. 35:279-299, 2000 Published 2000 Wiley-Liss, Inc.

Aminoquinolines↗
PubMed1999

Heterocyclic amine formation and the impact of structure on their mutagenicity.

The occurrence and formation of heterocyclic amines in foods is discussed in light of the consistent finding of a new class of imidazopyridines. In addition, a quantitative structure-activity relationship will be presented correlating the potency of these imidazopyridines to predicted chemical properties. Although no strong linear correlation is found between the potency and the chemical properties, a low dipole moment is found to be a qualitative predictor of high mutagenic potency.

Imidazoles↗
PubMed1998

Chemical and biological factors affecting mutagen potency.

This review surveys the chemical and biological factors that are correlated with the mutagenic activity of the aromatic and heterocyclic amines. Particular attention is given to the predicted quantum chemical properties of the parent amines and their metabolites. A number of chemical properties have been found to correlate well with measured mutagenic potency, including log P, the energies of the frontier orbitals of the parent amines, and the thermodynamic stability of the nitrenium ion, possibly the ultimate DNA-binding species. These correlations are intriguing clues to the mutagenic activity of the aromatic amines; however, many factors still await final explanation, including the exact mechanisms of the metabolic enzymes, the identity(s) of the ultimate DNA-binding species, the reaction mechanism in the DNA-adduction, the role of sequence context in the covalent and non-covalent binding of the adducts, and the role of DNA repair.

Animals↗
PubMed1997

Deprotonation and hydride shifts in nitrenium and iminium forms of aminoimidazole-azaarene mutagens.

The mutagenicity of many 2-aminoimidazole-azaarenes (AIA) is thought to be mediated by the nitrenium form of the exocyclic amine. This hypothesis is supported by the numerous correlations found between calculated and experimentally-measured chemical properties for the nitreniums and the mutagenic potencies of the nitreniums and their parent amines. One factor favoring high mutagenic potency is the presence of a methyl substituent in the 1- or 3-imidazole position. In this paper, we investigate both the deprotonation of the imidazole ring nitrogens in non-N-methylated AIA mutagens and the plausibility of a chemical pathway involving a 1-4 hydride shift to form an iminium ion, thereby stabilizing the cationic N-methyl substituted AIA mutagens. It has been widely noted that factors that stabilize the nitrenium moiety lead to significantly higher mutagenic potency; hence, the transformation of the nitrenium to a more stable species might be expected to increase the potency, provided that it does not eliminate the electrophilic reactivity of the compound. Using ab initio quantum chemistry and polarizable continuum solvation models, we find that the imidazole ring nitrogens of the nitrenium ions are extremely acidic. This suggests that upon formation of the exocyclic nitrenium these sites will deprotonate to form a neutral imine. We have also studied the 1-4 hydride shift from an imidazole ring methyl to the exocyclic nitrenium to form an iminium. We predict that for AIA mutagens with just two fused rings the resulting iminium species are more stable in the gas phase than the corresponding nitreniums. For mutagens with larger conjugated systems, the nitrenium is stabilized by resonance and is more stable than the corresponding iminium. In the aqueous phase, however, the iminium form is predicted to be more stable than the nitreniums for all polycyclic compounds studied. Although equilibrium calculations favor the iminium form, these have been experimentally shown to be short-lived and their actual concentration will depend on the complex kinetics of AIA mutagen metabolism. The quantum chemical results also show a strong correlation between the relative iminium-nitrenium energy difference and the charge on the exocyclic nitrogen.

Aza Compounds↗
PubMed1997

Quantitative structure-activity (QSAR) relationships of mutagenic aromatic and heterocyclic amines.

We extended our previous studies of mutagenic/carcinogenic heterocyclic aromatic amines formed during the cooking of foods to 66 aromatic and 99 heterocyclic amines for which mutagenic potency data are available. The amines require activation by enzymes to form metabolites reactive with DNA and exhibit an enormous range of potency as frameshift mutagens in the Ames/Salmonella assay. To ascertain factors that might influence potency, structural features and quantum mechanical parameters calculated by the Hückel method (and, for a subset of 20 amines, by semi-empirical AM1, and ab initio methods) were analyzed by multiple linear regression. The major findings were: (1) earlier findings on cooked food mutagens and their synthetic congeners can be extended to other amines; (2) mutagenic potency is directly related to the number of fused aromatic rings (size of the aromatic system), the number of ring nitrogen atoms (participation of lone electron pairs in the pi-cloud), and presence of a methyl substituent on a ring nitrogen; (3) potency is inversely related to the energy of the lowest unoccupied molecular orbital (LUMO) of the parent amine. Ford and Griffin (1992) and Sabbioni and Wild (1992) showed that the LUMO energy of the derived nitrenium ion is closely related to its stability (calculated with reference to aniline). Increased stability has been hypothesized to enhance the probability of adduct formation with DNA by avoiding detoxifying side reactions and increasing the lifetime of the ion. In the large heterogeneous series of amines in our present study the Hückel method energy of the highest occupied molecular orbital (HOMO), rather than the LUMO energy, of the nitrenium ion was marginally related to the potency of the parent amine. However, in the selected subset of 20 amines with ab initio calculation, the LUMO energy of the ion confirmed the previous reports. The contribution of quantum chemical factors to mechanistic insight on the mutagenicity and carcinogenicity of aromatic and heterocyclic amines is still under development.

Amines↗
PubMed1996

Structural and quantum chemical factors affecting mutagenic potency of aminoimidazo-azaarenes.

A set of 16 mutagenic aminoimidazo-azaarenes, including four that have been isolated from cooked foods and identified as bacterial mutagens and rodent carcinogens, was selected from a larger series previously published [Hatch et al. (1991): Environ Mol Mutagen 17:4-19] for an in-depth structure-activity study using computational methods. Structural features believed to affect mutagenic potency were tabulated. Molecular orbital energies and other electronic properties of these compounds were calculated using Huckel, semiempirical AM1, and ab initio quantum mechanical methods. Factor interrelationships were studied by multiple linear regression and canonical correlation analyses. Our goal was an improved understanding of the chemical basis of mutagenicity for this class of heterocyclic amines. The major findings were as follows: 1) mutagenic potency is related to the size of the aromatic ring system; 2) potency is enhanced by the presence and location of an N-methyl group; 3) potency is enhanced by addition of ring nitrogen atoms in pyridine, quinoline, and quinoxaline configurations; 4) potency is inversely related to the energy of the LUMO (lowest unoccupied molecular orbital) of the parent amines; 5) potency is directly, though weakly, related to the LUMO energy of the derived nitrenium ions; and 6) the calculated thermodynamic stability of the nitrenium ions (relative to the parent amine) is directly correlated with nitrenium LUMO energy and with the negative charge on the exocyclic nitrogen atom. Although this study raises several intriguing issues relating mutagenicity to chemical properties, further study will be required to determine the plausibility of the nitrenium ion as the ultimate mutagen for binding to DNA.

Benzimidazoles↗
PubMed1995

Structure-mutagenicity relationships of four amino-imidazonaphthyridines and imidazoquinolines.

We tested four isomeric imidazonaphthyridines and one imidazoquinoline compound for mutagenic activity in the Ames/Salmonella mutagenicity assay, using strain TA98 and strain YG1024, an analogue of strain TA98 with elevated O-acetyltransferase levels. Their potency was related to calculated electronic parameters. Five compounds with a linear arrangement of 3 rings showed a positive response in strain YG1024. Compound 2 (1-methylimidazo[4,5-b][1,7]naphthyridin-2-amine) is the most mutagenic in both strains, giving specific activities of about 200 and 30 revertants per microgram in strains YG1024 and TA98, respectively. Three of the compounds were weak mutagens, giving a positive dose-response only in strain YG1024, with 3-5 revertants per microgram. A higher response of all five compounds in strain YG1024 as opposed to TA98 indicates that they require O-acetyltransferase activity for their metabolism. Mutagenic potencies in strain YG1024 were positively correlated to the energy of the LUMO (lowest unoccupied molecular orbital) of the nitrenium ion.

Dose-Response Relationship, Drug↗
PubMed1995

Cancer risk of heterocyclic amines in cooked foods: an analysis and implications for research.

Heterocyclic amines (HAs) are formed as pyrolysis products during the cooking of meats/fish. These substances are potent mutagens in the Ames/Salmonella assay and are also carcinogens in laboratory animals. In order to assess the magnitude of the cancer risk posed by their presence in the US diet, we estimated the average intakes of HAs, based on analyses of the concentrations of HAs in cooked foods and data from a dietary survey of the US population and quantified the cancer potencies of the individual compounds using dose-response data from animal bioassays. Measured concentrations of HAs in cooked foods were taken from a major review of the open literature. Only those concentrations that were associated with normal cooking conditions were chosen for use in estimating dietary intakes. The average consumption of HA-bearing foods was determined by analyzing statistically the intakes of 3563 individuals who provided 3 day dietary records in a USDA sponsored random survey of the US population during 1989. Dietary intakes of the five principal HAs in descending order were 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) > 2-amino-9H-pyrido[2,3-b]indole (A alpha C) > 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) > 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) > 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). The carcinogenic potencies, in contrast, were almost the reverse order: IQ > DiMeIQx > MeIQx > PhIP > A alpha C. An upper-bound estimate of the incremental cancer risk is 1.1 x 10(-4), using cancer potencies based on a body surface area basis. Nearly half (46%) of the incremental risk was due to ingestion of PhIP. Consumption of meat and fish products contributed the most (approximately 80%) to total risk.

Amines↗
PubMed1995

Heterocyclic amine mutagenicity/carcinogenicity: influence of repair, metabolism, and structure.

Cooking, heat processing, and pyrolysis of protein-rich foods induce the formation of structurally related heterocyclic aromatic amines that have been found to be mutagenic in bacteria, mammalian cells in culture and mice. All these compounds are potent mutagens and most are active below 1 ng/plate, in Ames/Salmonella tester strain TA1538 in the presence of S9 liver microsomal preparations from rat, mouse, or hamster. They are also potent in strains TA98, TA97, moderately active in TA1537, weakly active in TA100, and virtually inactive in TA1535 and TA102. Thus, they show powerful frameshift activity in reverting specific GC-rich sequences, but do not cause base substitution mutations or revert an AT-rich sequence. They are 100-fold less active in the uvrB+, repair-proficient strain TA1978, and in the case of 2-amino-3-methylimidazo [4,5-f] quinoline (IQ), cause insertions and large deletions not seen in TA1538.

Amines↗
PubMed1992

Quantitative correlation of mutagenic and carcinogenic potencies for heterocyclic amines from cooked foods and additional aromatic amines.

Aromatic amines have long been recognized as animal and human carcinogens. Recently heterocyclic aromatic amines (thermic amines) have been found in small amounts in cooked foods, primarily meats, and have proven to be potent mutagens and rodent carcinogens. Availability of quantitative databases for mutagenic potency in Salmonella and for carcinogenic potency in rodents has made possible a study of ten heterocyclic thermic amines and 24 aromatic amines. Potencies on mutagenic and carcinogenic scales were significantly correlated. By multiple linear regression analysis and multivariate analysis of variance, two descriptive structural factors were found to modulate the two modes of biological response. These factors were number of rings and methyl substitution at carbon atoms. The quantitative correlation between mutagenic and carcinogenic potencies and the modulating structural factors suggest a significant similarity of molecular mechanisms and support the utility of the short-term bacterial assay in evaluating hazard levels.

Amines↗
PubMed1991

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

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.

Amines↗
PubMed1986

The isolation and identification of a new mutagen from fried ground beef: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).

A new mutagenic compound has been isolated from ground beef which was fried at 300 degrees C for 5.5 min on each side. The new mutagen was purified using an aqueous acid extraction, XAD-2 adsorption-solvent elution, a series of preparative and analytical h.p.l.c. purification steps, and monitored with the Ames/Salmonella assay. This study reveals a new mutagen member of the amino-imidazoazaarene class of aromatic amines, having a mol. w of 224, and a formula of C13H12N4 as determined by high-resolution mass spectrometry. N.m.r. spectrometry supports the structure, 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP), for the new mutagen. The 1-methyl and 3-methyl synthesized isomers of PhIP were compared to the purified mutagen. The two isomers had identical mass spectra to the purified compound, but only the 1-methyl isomer showed similar u.v. and n.m.r. spectra. The two synthetic isomers were separable by h.p.l.c. and the beef derived component co-eluted with the 1-methyl-PhIP isomer. PhIP has a specific activity in the Ames/Salmonella assay of 1950 revertants/microgram. Although it is not as mutagenic as other compounds isolated from fried beef (e.g. MeIQx, 58 000 revertants/microgram) it is the most abundant mutagenic compound by mass in fried beef. PhIP is present at approximately 15 p.p.b. of the original weight of uncooked beef (accounting for 75% of the mass of genotoxic material) and contributes 18% of the total mutagenicity of the fried beef.

Animals↗
PubMed1986

Identification of the mutagens in cooked beef.

The purification of cooking mutagens depends on the extraordinary sensitivity of the Ames/Salmonella mutagenicity test and its usefulness for tracking the mutagens during the purification steps. Following aqueous/acid (pH 2) extraction of fried ground beef (cooked at 200, 250, or 300 degrees C), XAD-2 column adsorption and elution with acetone, and acidic and basic liquid/liquid extractions, the samples are separated into six distinct peaks with preparative reverse-phase HPLC. A total of nine distinct mutagens can be separated after two additional HPLC steps. These compounds fall into a class of compounds called aminoimidazoazaarenes (AIAs). The majority of the mutagenic activity is made up of MeIQx1 (m/z 213, C11H11N5), DiMeIQx (m/z 227, C12H13N5), trimethylimidazopyridine (TMIP) (m/z 176, C9H12N4) and phenylimidazopyridine (PhIP) (m/z 224, C13H12N4). Smaller contributions are from IQ (m/z 198, C11H10N4), MeIQ (m/z 213, C12H12N4), a nonpolar peak containing oxygen and two unidentified trace polar mutagens. Mass estimates (per kilogram uncooked beef) include: 15 micrograms for PhIP, 1.0 micrograms for MeIQx, 0.5 microgram for DiMeIQx, and 0.02 microgram for IQ. Because of the uncoupling of mutagenic and carcinogenic potencies of these aromatic amines, the PhIP, which contributes the highest mass content to the cooked meat, but has the lowest mutagenic potency, might ultimately make a significant contribution to the carcinogenicity.

Animals↗
PubMed1986

A current genotoxicity database for heterocyclic thermic food mutagens. I. Genetically relevant endpoints.

Cooking, heat processing, or pyrolysis of protein-rich foods induce the formation of a series of structurally related heterocyclic aromatic bases that have been found to be mutagens. The primary genetic assay utilized to detect and isolate these mutagens has been the his reversion assay in Salmonella typhimurium. The classification and nomenclature of these chemicals is revised to reflect recent advances. The findings of short-term tests for genetic injury that have been applied to these agents are presented in a systematic way. Cell-free, bacterial, mammalian cell culture, and in vivo systems are included. Major results, the mutagens tested, and key references are presented in tabular form, with text commentary. Integrated conclusions on the state of current knowledge of the genetic toxicity of thermic food mutagens are presented. Areas in need of further research are defined. Finally, an outline is presented of a suggested path leading to the determination whether normal methods of food preparation and processing constitute a human health hazard.

Animals↗