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Robert J. Turesky - One of the best experts on this subject based on the ideXlab platform.
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neuromelanin modulates heterocyclic Aromatic Amine induced dopAminergic neurotoxicity
Toxicological Sciences, 2020Co-Authors: Robert J. Turesky, Vivek Lawana, Jeanchristophe Rochet, Jonathan H Shannahan, Jason R CannonAbstract:Heterocyclic Aromatic Amines (HAAs) are mutagens and potential human carcinogens. Our group and others have demonstrated that HAAs may also produce selective dopAminergic neurotoxicity, potentially relevant to Parkinson's disease (PD). The goal of this study was to elucidate mechanisms of HAA-induced neurotoxicity through examining a translational biochemical weakness of common PD models. Neuromelanin is a pigmented byproduct of dopAmine metabolism that has been debated as being both neurotoxic and neuroprotective in PD. Importantly, neuromelanin is known to bind and potentially release dopAminergic neurotoxicants, including HAAs (eg, β-carbolines such as harmane). Binding of other HAA subclasses (ie, aminoimidazoaazarenes) to neuromelanin has not been investigated, nor has a specific role for neuromelanin in mediating HAA-induced neurotoxicity been exAmined. Thus, we investigated the role of neuromelanin in modulating HAA-induced neurotoxicity. We characterized melanin from Sepia officinalis and synthetic dopAmine melanin, proposed neuromelanin analogs with similar biophysical properties. Using a cell-free assay, we demonstrated strong binding of harmane and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to neuromelanin analogs. To increase cellular neuromelanin, we transfected SH-SY5Y neuroblastoma cells with tyrosinase. Relative to controls, tyrosinase-expressing cells exhibited increased neuromelanin levels, cellular HAA uptake, cell toxicity, and oxidative damage. Given that typical cellular and rodent PD models form far lower neuromelanin levels than humans, there is a critical translational weakness in assessing HAA-neurotoxicity. The primary impacts of these results are identification of a potential mechanism by which HAAs accumulate in catecholAminergic neurons and support for the need to conduct neurotoxicity studies in systems forming neuromelanin.
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Formation and analysis of heterocyclic Aromatic Amine-DNA adducts in vitro and in vivo.
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2004Co-Authors: Robert J. Turesky, Paul VourosAbstract:The detection and quantification of heterocyclic Aromatic Amine (HAA)-DNA adducts, critical biomarkers in interspecies extrapolation of toxicity data for human risk assessment, remains a challenging analytical problem. The two main analytical methods currently in use to screen for HAA-DNA adducts are the 32P-postlabeling assay and mass spectrometry, using either accelerated mass spectrometry (AMS) or liquid chromatography and electrospray ionization mass spectrometry (LC-ESI-MS). In this review, the principal methods to synthesize and characterize DNA adducts, and the methods applied to measure HAA-DNA adduct in vitro and vivo are discussed.
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heterocyclic Aromatic Amine metabolism dna adduct formation mutagenesis and carcinogenesis
Drug Metabolism Reviews, 2002Co-Authors: Robert J. TureskyAbstract:Heterocyclic Aromatic Amines (HAAs) are carcinogenic compounds formed in meats, fish, and poultry prepared under common household cooking practices. Some HAAs are also formed in tobacco smoke condensate. Because of the widespread occurrence of HAAs in these daily staples, health concerns have been raised regarding the potential role of HAAs in the etiology of some human cancers associated with frequent consumption of these products. In this review, the metabolism of HAAs to biologically active metabolites that bind to DNA and provoke mutations and cancer in various biological systems is discussed. Some of the current analytical and molecular methods that are used to measure biomarkers of HAA exposure and genetic damage in experimental animal models and humans are also presented. These biochemical data combined may help to better assess the role that HAAs may have in the development of some common forms of human cancers.
Francisco J Hidalgo - One of the best experts on this subject based on the ideXlab platform.
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reactive carbonyls and the formation of the heterocyclic Aromatic Amine 2 amino 3 4 dimethylimidazo 4 5 f quinoline meiq
Food Chemistry, 2020Co-Authors: Rosario Zamora, Cristina M Lavadotena, Francisco J HidalgoAbstract:Abstract Reactions involving reactive carbonyls, creatinine, and ammonia-producing compounds were investigated in order to clarify the formation of the heterocyclic Aromatic Amine (HAA) 2-amino-3,4-dimethylimidazo(4,5-f)quinoline (MeIQ). Obtained results showed that MeIQ was only produced when 2-butenal (crotonaldehyde) was present. Reaction yields depended on the pH, with a maximum around pH 6.5, and on concentrations of crotonaldehyde and creatinine. Ammonia was also required for MeIQ formation, but ammonia was produced by creatinine decomposition. The amount of MeIQ formed increased with reaction time, temperature, and oxygen content in the reaction atmosphere. Activation energy for MeIQ formation from crotonaldehyde, creatinine, and glutAmine was 72.2 ± 0.4 kJ·mol−1. A reaction pathway that explains MeIQ formation is proposed. Obtained results suggest a main role of reactive carbonyls formed in foods (the food carbonylome) on HAA formation. In addition, they provide scientific basis for the understanding of how HAAs are formed and could be mitigated.
David W Hein - One of the best experts on this subject based on the ideXlab platform.
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catalytic properties and heat stabilities of novel recombinant human n acetyltransferase 2 allozymes support existence of genetic heterogeneity within the slow acetylator phenotype
Archives of Toxicology, 2017Co-Authors: David W Hein, Mark A DollAbstract:Human N-acetyltransferase 2 (NAT2) catalyzes the N-acetylation of numerous Aromatic Amine drugs such as sulfamethazine (SMZ) and hydrazine drugs such as isoniazid (INH). NAT2 also catalyzes the N-acetylation of Aromatic Amine carcinogens such as 2-aminofluorene and the O- and N,O-acetylation of Aromatic Amine and heterocyclic Amine metabolites. Genetic polymorphism in NAT2 modifies drug efficacy and toxicity as well as cancer risk. Acetyltransferase catalytic activities and heat stability associated with six novel NAT2 haplotypes (NAT2*6C, NAT2*14C, NAT2*14D, NAT2*14E, NAT2*17, and NAT2*18) were compared with that of the reference NAT2*4 haplotype following recombinant expression in Escherichia coli. N-acetyltransferase activities towards SMZ and INH were significantly (p 0.05) from recombinant NAT2 4. The apparent Vmax catalyzed by NAT2 14C and NAT2 14D were significantly lower (p < 0.05) than the apparent Vmax catalyzed by NAT2 6C and NAT2 14E towards AF, ABP, and DMABP. Heat inactivation rate constants for recombinant human NAT2 14C, 14D, 14E, and 18 were significantly (p < 0.05) higher than NAT2 4. These results provide further evidence of genetic heterogeneity within the NAT2 slow acetylator phenotype.
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molecular genetics and function of nat1 and nat2 role in Aromatic Amine metabolism and carcinogenesis
Mutation Research, 2002Co-Authors: David W HeinAbstract:Aromatic and heterocyclic Amines require metabolic activation to electrophilic intermediates that initiate carcinogenesis. N-Acetyltransferase 1 (NAT1) and 2 (NAT2) are important enzymes in the biotransformation of these carcinogens and exhibit genetic polymorphism. Human NAT1 and NAT2 alleles are listed at: http://www.louisville.edu/medschool/pharmacology/NAT.html by an international gene nomenclature committee. The high frequency of the NAT1 and NAT2 acetylation polymorphisms in human populations together with ubiquitous exposure to Aromatic and heterocyclic Amines suggest that NAT1 and NAT2 acetylator genotypes are important modifiers of human cancer susceptibility. For cancers in which N-acetylation is a detoxification step such as Aromatic Amine-related urinary bladder cancer, NAT2 slow acetylator phenotype is at higher risk. Multiple studies have shown that the urinary bladder cancer risk is particularly high in the slowest NAT2 acetylator phenotype or genotype (NAT2(*)5). In contrast, for cancers in which N-acetylation is negligible and O-acetylation is an activation step such as for heterocyclic Amine-related colon cancer, NAT2 rapid acetylator phenotype is at higher risk. Although studies have found associations between NAT1 genotype and various cancers, the findings are less consistent and are not well understood. Since cancer risk requires exposure to Aromatic and/or heterocyclic Amine carcinogens modified by NAT1 and/or NAT2 acetylator genotype, the results from human epidemiology studies are dependent upon the quality and accuracy of the exposure assessment and genotype determination. Conclusions require understanding the relationship between genotype and phenotype, as well as the role of genetic variation in carcinogen metabolism, DNA repair, and host susceptibility. Investigations have been carried out in rapid and slow acetylator rodent models in which both exposure and genetic variability are tightly controlled. Human NAT1 and NAT2 alleles have been characterized by recombinant expression to further understand the effects of nucleotide polymorphisms on function and phenotype.
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cloning sequencing and recombinant expression of nat1 nat2 and nat3 derived from the c3h hej rapid and a hej slow acetylator inbred mouse functional characterization of the activation and deactivation of Aromatic Amine carcinogens
Toxicology and Applied Pharmacology, 1997Co-Authors: Adrian J Fretland, Mark A Doll, Kevin Gray, Yi Feng, David W HeinAbstract:An acetylator polymorphism has been described in the mouse and the inbred strains C3H/HeJ and A/HeJ constitute rapid and slow acetylators, respectively. The NAT1, NAT2, and NAT3 genes from C3H/HeJ and A/HeJ acetylator inbred mouse strains were amplified using the polymerase chain reaction, cloned into the plasmid vector pUC19, and sequenced. They were then subcloned into the prokaryotic expression vector pKK223-3 and expressed in Escherichia coli strain JM105. The 870-bp nucleotide coding region of NAT1 and NAT3 did not differ between the rapid and slow acetylator mouse strains, or from that of previously published mouse NAT1 and NAT3 sequences. However, NAT2 did differ between the rapid and slow acetylator strains with an A296 T transition which causes a (Asn99-->Ile) substitution in the deduced amino acid sequence. Recombinant NAT1, NAT2, and NAT3 proteins catalyzed N-, O-, and N,O-acetyltransferase activities. NAT3 catalyzed Aromatic Amine N-acetyltransferase activities at very low rates, which confirms a previous study. Apparent K(m) and Vmax kinetic constants for N-acetylation were 5- to 10-fold lower for recombinant mouse NAT1 than NAT2. Intrinsic clearances for recombinant mouse NAT1- and NAT2-catalyzed N-acetylation of Aromatic Amine carcinogens were comparable. Both recombinant mouse NAT1 and NAT2 catalyzed the metabolic activation of N-hydroxyarylAmine (O-acetylation) and N-hydroxyarylamide (N,O-acetylation) carcinogens. Recombinant mouse NAT3 catalyzed N,O-acetylation at very low rates, while O-acetylation was undetectable. No difference was observed between rapid and slow acetylator recombinant NAT2 proteins to activate Aromatic Amines by O- or N,O-acetylation, in substrate specificity, expression of immunoreactive protein, electrophoretic mobility, or N-acetyltransferase Michaelis-Menten kinetic constants. However, the slow acetylator recombinant NAT2 protein was over 10-fold less stable than rapid acetylator recombinant NAT2. These studies demonstrate metabolic activation and deactivation by recombinant mouse NAT1, NAT2, and NAT3 proteins and confirm and extend previous studies on the molecular basis for the acetylation polymorphism in the mouse.
Rosario Zamora - One of the best experts on this subject based on the ideXlab platform.
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reactive carbonyls and the formation of the heterocyclic Aromatic Amine 2 amino 3 4 dimethylimidazo 4 5 f quinoline meiq
Food Chemistry, 2020Co-Authors: Rosario Zamora, Cristina M Lavadotena, Francisco J HidalgoAbstract:Abstract Reactions involving reactive carbonyls, creatinine, and ammonia-producing compounds were investigated in order to clarify the formation of the heterocyclic Aromatic Amine (HAA) 2-amino-3,4-dimethylimidazo(4,5-f)quinoline (MeIQ). Obtained results showed that MeIQ was only produced when 2-butenal (crotonaldehyde) was present. Reaction yields depended on the pH, with a maximum around pH 6.5, and on concentrations of crotonaldehyde and creatinine. Ammonia was also required for MeIQ formation, but ammonia was produced by creatinine decomposition. The amount of MeIQ formed increased with reaction time, temperature, and oxygen content in the reaction atmosphere. Activation energy for MeIQ formation from crotonaldehyde, creatinine, and glutAmine was 72.2 ± 0.4 kJ·mol−1. A reaction pathway that explains MeIQ formation is proposed. Obtained results suggest a main role of reactive carbonyls formed in foods (the food carbonylome) on HAA formation. In addition, they provide scientific basis for the understanding of how HAAs are formed and could be mitigated.
Shobana Murugesan - One of the best experts on this subject based on the ideXlab platform.
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sequential anaerobic aerobic treatment using plant microbe integrated system for degradation of azo dyes and their Aromatic Amines by products
Journal of Hazardous Materials, 2018Co-Authors: Mohanapriya Jayapal, Hema Jagadeesan, Manoj Kumar Shanmugam, Perinba Danisha J, Shobana MurugesanAbstract:Abstract The presence of unused dyes and dye degradation intermediates in the textile industry wastewaters is the major challenge in its treatment. A wide range of treatments including various physicochemical processes are used for this wastewater. Incomplete dye degradation results in hazardous colorless Aromatic Amine intermediates that are teratogenic in nature. A synergistic plant-microbe system operated in a sequential anaerobic-aerobic mode was evaluated for the complete degradation of a model azo dye methyl red under laboratory conditions. The degradation of methyl red and its break down products 2-aminobenzoic acid and N,N-dimethyl-p-phenylenediAmine were analysed by HPLC, FTIR and GC–MS. The vetiver-microbe system had shown enhanced dye degradation. The dye decolourization percentage achieved for integrated plant-microbe treatment system (T) after anaerobic condition was 53.5 ± 6.2% and aerobic condition was 92 ± 3.4%. The removal efficiency of the intermediates 2-ABA and DMPD was found to be 89.79% in the integrated plant-microbe treatment system. The plant-microbe system was most effective in the removal of toxic Aromatic Amine as seen by lesser phytotoxicity for seed germination and teratogenicity in case of zebrafish development in the treated water.