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1-Nitronaphthalene

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Charles G. Plopper – One of the best experts on this subject based on the ideXlab platform.

  • Identification of proteins adducted by reactive metabolites of naphthalene and 1-Nitronaphthalene in dissected airways of rhesus macaques.
    Proteomics, 2006
    Co-Authors: Ching Yu Lin, Dexter Morin, Charles G. Plopper, Bridget C. Boland, Lisa A. Miller, Young Jin Lee, Michelle Salemi, Alan R. Buckpitt
    Abstract:

    Naphthalene and 1-Nitronaphthalene are ambient air pollutants, which undergo P450-dependent bioactivation in the lung. Reactive metabolites of naphthalene and 1-Nitronaphthalene covalently bind to proteins, and the formation of covalent adducts correlates with airway epithelial cell injury in rodent models. These studies were designed to identify protein adducts generated from these reactive metabolites within distal respiratory airways. Distal bronchioles and parenchyma from rhesus monkeys were incubated with [(14)C]naphthalene or [(14)C]1-Nitronaphthalene. Proteins were separated by 2-DE, blotted to PVDF membranes, and adducted proteins imaged by storage phosphosphor analysis. MS of in-gel tryptic digests identified numerous adducted proteins including: eight cytoskeletal protproteins, two chaperone proteins, seven metabolic enzymes, one redox protein, two proteins involved in ion balance and cell signaling, and two extracellular proteins. While many proteins are adducted by both naphthalene and 1-Nitronaphthalene, some are unique to the individual toxicant and airway subcompartment. Although the role which adduction of these proteins plays in cytotoxicity was not evaluated, these studies provide candidate proteins for future work designed to determine the importance of protein adducts in the mechanisms of toxicity and for developing biomarkers useful in determining the relevance of findings in animal models to exposed human populations.

  • Increased vulnerability of neonatal rats and mice to 1-Nitronaphthalene-induced pulmonary injury ☆
    Toxicology and applied pharmacology, 2004
    Co-Authors: Michelle V. Fanucchi, Kimberly C. Day, Candice C. Clay, Charles G. Plopper
    Abstract:

    The postnatal period of lung development is a critical window of susceptibility to environmental toxicants, including polyaromatic hydrocarbons (PAHs) and furans. To determine whether the increased susceptibility of neonatal lung injury due to environmental toxicants is a universal response across species and also applies to nitrated compounds, adult and 7-day-old male mice and rats were given a single intraperitoneal dose (0, 12.5, 25, 50, or 100 mg/kg) of 1-Nitronaphthalene and killed 24 h later. Exposure to 1-Nitronaphthalene, a nitro-polyaromatic hydrocarbon, results in pulmonary lesions in both adult rats and mice, although the severity of the injury is species-specific (greater in rats than in mice). Pulmonary lesions, as assessed by quantitative histopathology, included dose-dependent vacuolization and exfoliation of both ciliated and nonciliated airway epithelial cells throughout the airway tree in both rats and mice. In both species, the 7-day-old animals were more susceptible to injury by 1-Nitronaphthalene than adult animals. In contrast to adult response, neonatal mice were more susceptible to 1-Nitronaphthalene-induced pulmonary injury than neonatal rats. This indicates that neonatal susceptibility to environmental pollutant-induced lung injury cannot be reliably predicted based on adult susceptibility.

  • Site-Specific Metabolism of Naphthalene and 1-Nitronaphthalene in Dissected Airways of Rhesus Macaques
    The Journal of pharmacology and experimental therapeutics, 2004
    Co-Authors: Bridget C. Boland, Ching Yu Lin, Dexter Morin, Charles G. Plopper, Lisa A. Miller, Alan R. Buckpitt
    Abstract:

    Studies in rodents have demonstrated the importance of cytochrome P450 monooxygenases in generating reactive metabolites that produce Clara cell injury. Pulmonary P450 activities in rodents are much higher than those in primates, raising the issue of relevance of rodent data to primates. Few studies on P450-catalyzed activation of cytotoxicants in subcompartments of primate lung have been reported. Accordingly, infant monkey airway subcompartments, including trachea, proximal, midlevel, distal airways, and parenchyma, were incubated with naphthalene or 1-Nitronaphthalene to define metabolism at both high (500 microM) and low (50 microM) substrate concentrations. There was a relatively even distribution of metabolizing activities for naphthalene across subcompartments, but at high concentrations of 1-Nitronaphthalene, lower airways (midlevel airway through parenchyma) showed higher bioactivation than upper airways. Dihydrodiol was the predominant water-soluble metabolite of naphthalene generated by all subcompartments, whereas covalently bound metabolites accounted for the greatest percentage of 1-Nitronaphthalene metabolites, especially in lower airways. As anticipated, the amounts of metabolite covalently bound as a percentage of total metabolite formed increased dramatically with the 10-fold increase in substrate concentration. With both substrates, the formation of water-soluble metabolites was approximately 100 times less than observed previously in rodents. We conclude that 1) there are significant quantitative differences between rhesus and rodents in substrate bioactivation; 2) the distribution of metabolizing activities for naphthalene but not 1-Nitronaphthalene is significantly different for rodents and primates; and 3) a very high percentage of the metabolites generated, particularly for 1-Nitronaphthalene, is bound covalently to cellular proteins.

Carlos E. Crespo-hernández – One of the best experts on this subject based on the ideXlab platform.

  • Conformational control in the population of the triplet state and photoreactivity of nitronaphthalene derivatives.
    The journal of physical chemistry. A, 2013
    Co-Authors: R. A. Vogt, Carlos E. Crespo-hernández
    Abstract:

    Nitronaphthalene derivatives (NNDs) are among the most abundant volatile nitro-polycyclic aromatic hydrocarbons found in the Earth’s atmosphere. Investigations of the atmospheric degradation processes show that photolysis is the major degradation pathway under ambient conditions. In this contribution, we present photochemical measurements and quantum-chemical calculations of three major NNDs. It is shown that the magnitude of the photodegradation and triplet quantum yields in 1-Nitronaphthalene (1NN), 2-methyl-1-Nitronaphthalene (2M1NN), and 2-nitronaphthalene (2NN) are inversely related to each other. In accord with a recent time-resolved and computation study (J. Phys. Chem. A 2013, 117, 6580) and in order to explain this striking observation we propose that these photochemical yields are largely controlled by (1) the conformational heterogeneity of the nitro-aromatic torsion angle, (2) the energy gap (spin–orbit coupling interaction) between the excited singlet state and the receiver triplet state, and…

  • Excited-state dynamics in nitro-naphthalene derivatives: intersystem crossing to the triplet manifold in hundreds of femtoseconds.
    The journal of physical chemistry. A, 2013
    Co-Authors: R. Aaron Vogt, Christian Reichardt, Carlos E. Crespo-hernández
    Abstract:

    Femtosecond transient absorption experiments and density functional calculations are presented for 2-methyl-1-Nitronaphthalene, 2-nitronaphthalene, and 1-Nitronaphthalene in cyclohexane and acetonitrile solutions. Excitation of 2-methyl-1-Nitronaphthalene at 340 nm populates the Franck–Condon singlet state, which bifurcates into two barrierless decay channels with sub-200-fs lifetimes. The primary decay channel connects the Franck–Condon singlet excited state with a receiver triplet state, whereas the second, minor channel involves conformational relaxation to populate an intramolecular charge-transfer state, as previously reported for 1-Nitronaphthalene (J. Chem. Phys. 2009, 113, 224518). Conversely, the experimental and computational data for 2-nitronaphthalene shows that almost the entire Franck–Condon singlet excited-state population intersystem crosses to the triplet state in less than 200 fs due to a sizable energy barrier of ca. 5 kcal/mol that must be surmounted to access the intramolecular charge…

  • On the Primary Reaction Pathways in the Photochemistry of Nitro-Polycyclic Aromatic Hydrocarbons
    Modern Chemistry & Applications, 2013
    Co-Authors: Carlos E. Crespo-hernández, Aaron Vogt R, Briana Sealey
    Abstract:

    The primary reaction pathways in the photochemistry of nitro-polycyclic aromatic hydrocarbons under specific laboratory conditions are briefly summarized. In addition, photochemical data is presented for 2-nitronaphthalene, 1-Nitronaphthalene, and 2-methyl-1-Nitronaphthalene in cyclohexane and acetonitrile solutions under aerobic and anaerobic conditions. It is shown that molecular oxygen significantly reduces the photodegradation quantum yield of 1-Nitronaphthalene and 2-methyl-1-Nitronaphthalene by 63% and 81%, respectively, whereas 2-nitronaphthalene is photoinert in both solvents under aerobic and anaerobic conditions. In addition, it is proposed that recombination of the aryl and nitrogen (IV) dioxide geminate radical pair within the solvent cage or internal conversion of an initially formed intramolecular charge transfer state may play an important role in the fraction of excited molecules that returns to the ground state in 1-Nitronaphthalene and 2-methyl-1-Nitronaphthalene. Scavenging of radical species by molecular oxygen and the generation of singlet oxygen in high yield are proposed to contribute to the photochemistry of these nitro-naphthalene derivatives in solution.

Alan R. Buckpitt – One of the best experts on this subject based on the ideXlab platform.

  • Identification of proteins adducted by reactive metabolites of naphthalene and 1-Nitronaphthalene in dissected airways of rhesus macaques.
    Proteomics, 2006
    Co-Authors: Ching Yu Lin, Dexter Morin, Charles G. Plopper, Bridget C. Boland, Lisa A. Miller, Young Jin Lee, Michelle Salemi, Alan R. Buckpitt
    Abstract:

    Naphthalene and 1-Nitronaphthalene are ambient air pollutants, which undergo P450-dependent bioactivation in the lung. Reactive metabolites of naphthalene and 1-Nitronaphthalene covalently bind to proteins, and the formation of covalent adducts correlates with airway epithelial cell injury in rodent models. These studies were designed to identify protein adducts generated from these reactive metabolites within distal respiratory airways. Distal bronchioles and parenchyma from rhesus monkeys were incubated with [(14)C]naphthalene or [(14)C]1-Nitronaphthalene. Proteins were separated by 2-DE, blotted to PVDF membranes, and adducted proteins imaged by storage phosphor analysis. MS of in-gel tryptic digests identified numerous adducted proteins including: eight cytoskeletal proteins, two chaperone proteins, seven metabolic enzymes, one redox protein, two proteins involved in ion balance and cell signaling, and two extracellular proteins. While many proteins are adducted by both naphthalene and 1-Nitronaphthalene, some are unique to the individual toxicant and airway subcompartment. Although the role which adduction of these proteins plays in cytotoxicity was not evaluated, these studies provide candidate proteins for future work designed to determine the importance of protein adducts in the mechanisms of toxicity and for developing biomarkers useful in determining the relevance of findings in animal models to exposed human populations.

  • Bioactivation of the pulmonary toxicants naphthalene and 1-Nitronaphthalene by rat CYP2F4.
    The Journal of pharmacology and experimental therapeutics, 2004
    Co-Authors: R Michael Baldwin, Michael A. Shultz, Alan R. Buckpitt
    Abstract:

    Naphthalene, a ubiquitous environmental contaminant, produces cytotoxicity in nonciliated bronchiolar epithelial (Clara) cells in mice; rats are refractory to lung cytotoxicity from naphthalene. In contrast, 1-Nitronaphthalene is a potent toxicant in both species. Naphthalene is metabolized by CYP2F to a 1,2-epoxide, the first and obligate step in events leading to cytotoxicity. 1-Nitronaphthalene is metabolized to both the 5,6- and the 7,8-epoxides with the 7,8-epoxide predominating in lung. Previous studies have demonstrated recombinant CYP2F2 (mouse) to efficiently metabolize both naphthalene and 1-Nitronaphthalene. To better understand the mechanism for the unique toxicity profiles for both compounds, a CYP2F ortholog (CYP2F4) was isolated from rat lung and expressed using a baculovirus system. Recombinant CYP2F4 efficiently generates 1R,2S-naphthalene oxide (K(m) = 3 microM, V(max) = 107 min(-1)) and the 5,6- and 7,8-epoxides of 1-Nitronaphthalene (K(m) = 18 microM, V(max) = 25 min(-1) based on total generated glutathione conjugates). Kinetics and regio/stereoselectivity of rat CYP2F4 were indistinguishable from mouse CYP2F2. These results, combined with our recent immunomapping studies demonstrating minimal pulmonary CYP2F expression in rats, indicate that CYP2F expression is the factor most clearly associated with susceptibility to naphthalene-induced pneumotoxicity. CYP2F4 failed to display an enhanced ability to bioactivate 1-Nitronaphthalene, an ability that could have potentially compensated for the lower CYP2F pulmonary expression levels in the rat, yet equal species susceptibilities. These results suggest the importance of other P450 enzymes in the epoxidation/bioactivation of 1-Nitronaphthalene. Expression of recombinant CYP2F1 (human) yielded an immunoreactive protein with no detectable CO-difference spectrum suggesting inadequate heme incorporation.

  • Site-Specific Metabolism of Naphthalene and 1-Nitronaphthalene in Dissected Airways of Rhesus Macaques
    The Journal of pharmacology and experimental therapeutics, 2004
    Co-Authors: Bridget C. Boland, Ching Yu Lin, Dexter Morin, Charles G. Plopper, Lisa A. Miller, Alan R. Buckpitt
    Abstract:

    Studies in rodents have demonstrated the importance of cytochrome P450 monooxygenases in generating reactive metabolites that produce Clara cell injury. Pulmonary P450 activities in rodents are much higher than those in primates, raising the issue of relevance of rodent data to primates. Few studies on P450-catalyzed activation of cytotoxicants in subcompartments of primate lung have been reported. Accordingly, infant monkey airway subcompartments, including trachea, proximal, midlevel, distal airways, and parenchyma, were incubated with naphthalene or 1-Nitronaphthalene to define metabolism at both high (500 microM) and low (50 microM) substrate concentrations. There was a relatively even distribution of metabolizing activities for naphthalene across subcompartments, but at high concentrations of 1-Nitronaphthalene, lower airways (midlevel airway through parenchyma) showed higher bioactivation than upper airways. Dihydrodiol was the predominant water-soluble metabolite of naphthalene generated by all subcompartments, whereas covalently bound metabolites accounted for the greatest percentage of 1-Nitronaphthalene metabolites, especially in lower airways. As anticipated, the amounts of metabolite covalently bound as a percentage of total metabolite formed increased dramatically with the 10-fold increase in substrate concentration. With both substrates, the formation of water-soluble metabolites was approximately 100 times less than observed previously in rodents. We conclude that 1) there are significant quantitative differences between rhesus and rodents in substrate bioactivation; 2) the distribution of metabolizing activities for naphthalene but not 1-Nitronaphthalene is significantly different for rodents and primates; and 3) a very high percentage of the metabolites generated, particularly for 1-Nitronaphthalene, is bound covalently to cellular proteins.

Jorge Peon – One of the best experts on this subject based on the ideXlab platform.

  • excited state dynamics of nitrated push pull molecules the importance of the relative energy of the singlet and triplet manifolds
    Journal of Physical Chemistry A, 2009
    Co-Authors: Elisa Colladofregoso, Jimena S Zugazagoitia, Eddy F Plazamedina, Jorge Peon
    Abstract:

    We present a study of the dynamics following photoexcitation in the first electronic band of NO2-para-substituted nitronaphthalenes. Our main goal was to determine the interplay between the nitro group, electron-donating substituents, and the solvent in defining the relative excited-state energies and their photoinduced pathways. We studied 4-nitro-1-naphthylamine and 1-methoxy-4-nitronaphthalene in solution samples through femtosecond fluorescence up-conversion and transient absorption techniques. In all solvents, both compounds have ultrafast fluorescence decays, showing that, similarly to the parent compound 1-Nitronaphthalene, these molecules have highly efficient S1 decay channels. The evolution of the transient absorption signals in the visible region reveals that for the methoxy-substituted compound, independently of solvent polarity, the photophysical pathways are the same as in 1-Nitronaphthalene, namely, ultrafast intersystem crossing to an upper triplet state (receiver Tn state) followed by rel…

  • Relaxation in the Triplet Manifold of 1-Nitronaphthalene Observed by Transient Absorption Spectroscopy
    The journal of physical chemistry. A, 2009
    Co-Authors: Jimena S Zugazagoitia, Elisa Collado-fregoso, Eddy F. Plaza-medina, Jorge Peon
    Abstract:

    Previous phosphorescence and triplet quantum yield determinations indicate that the primary photophysical channel for 1-Nitronaphthalene is the formation of its lowest energy triplet state. Also, previous direct measurements of the decay of the fluorescence from this compound indicated that the crossing between the singlet and triplet manifolds is ultrafast (sub-100 fs). In this contribution we present a sub-picosecond transient absorption study of the relaxation of photoexcited 1-Nitronaphthalene in methanol and other solvents. Our measurements reveal the time scale in which the fully relaxed T1 state is formed. We have observed that the spectral evolution associated with this process takes place in time scales from one to a few tens of picoseconds. Specifically, the appearance of the absorption spectrum of T1 in the visible region is accompanied by the decay of transient signals at wavelengths below 400 nm. Since the fluorescence lifetime of this compound is sub-100 fs, we assigned the picoseconds decay…

  • Ultrafast Intersystem Crossing in 1-Nitronaphthalene. An Experimental and Computational Study
    The journal of physical chemistry. A, 2008
    Co-Authors: Jimena S Zugazagoitia, César Xavier Almora-diaz, Jorge Peon
    Abstract:

    Previous studies have established that the major pathway for the first singlet excited state of 1-Nitronaphthalene is intersystem crossing to the triplet manifold. In this contribution we present determinations of the decay of the S1 state of this compound in several solvents to establish the time scale of the multiplicity change as a function of the polarity and hydrogen-bonding ability of the solvent environment. The measurements were made with the femtosecond frequency up-conversion technique to follow the weak spontaneous molecular emission which precedes triplet formation. Our results show that in all environments the S1 lifetime is 100 fs or less, making 1-Nitronaphthalene the organic compound with the fastest multiplicity change ever measured. We also show that the bathochromic shifts observed for the first absorption band imply changes in the relative energies of the singlet and triplet manifolds, which in turn manifest in a 2-fold increase of the fluorescence lifetime in cyclohexane compared with…

Dexter Morin – One of the best experts on this subject based on the ideXlab platform.

  • Toxicity and metabolism of methylnaphthalenes: comparison with naphthalene and 1-Nitronaphthalene.
    Toxicology, 2009
    Co-Authors: Ching Yu Lin, Asa M Wheelock, Dexter Morin, R Michael Baldwin, Myong Gong Lee, Aysha Taff, Charles Plopper, Alan Buckpitt, Arlean Rohde
    Abstract:

    Naphthalene and close structural analogues have been shown to cause necrosis of bronchiolar epithelial cells in mice by both inhalation exposure and by systemic administration. Cancer bioassays of naphthalene in mice have demonstrated a slight increase in bronchiolar/alveolar adenomas in female mice, and in inflammation and metaplasia of the olfactory epithelium in the nasal cavity. Similar work in rats demonstrated a significant, and concentration-dependent increase in the incidence of respiratory epithelial adenomas and neuroblastomas in the nasal epithelium of both male and female rats. Although the studies on the acute toxicity of the methylnaphthalene derivatives are more limited, it appears that the species selective toxicity associated with naphthalene administration also is observed with methylnaphthalenes. Chronic administration of the methylnaphthalenes, however, failed to demonstrate the same oncogenic potential as that observed with naphthalene. The information available on the isopropylnaphthalene derivatives suggests that they are not cytotoxic. Like the methylnaphthalenes, 1-Nitronaphthalene causes lesions in both Clara and ciliated cells. However, the species selective lung toxicity observed in the mouse with both naphthalene and the methylnaphthalenes is not seen with 1-Nitronaphthalene. With 1-Nitronaphthalene, the rat is far more susceptible to parenteral administration of the compound than mice. The wide-spread distribution of these compounds in the environment and the high potential for low level exposure to humans supports a need for further work on the mechanisms of toxicity in animal models with attention to whether these processes are applicable to humans. Although it is tempting to suppose that the toxicity and mechanisms of toxicity of the alkylnaphthalenes and nitronaphthalenes are similar to naphthalene, there is sufficient published literature to suggest that this may not be the case. Certainly the enzymes involved in the metabolic activation of each of these substrates are likely to differ. The available data showing extensive oxidation of the aromatic nucleus of naphthalene, nitronaphthalene and the methylnaphthalenes (with some oxidation of the methyl group) contrast with the isopropylnaphthalene derivatives, where the major metabolites involve side chain oxidation. Overall, these data support the view that ring epoxidation is a key step in the process involved in cytotoxicity. Whether the epoxide itself or a downstream metabolite mediates the toxic effects is still not clear even with naphthalene, the best studied of this group of compounds. Additional work is needed in several areas to further assess the potential human healhealth consequences of exposure to these agents. These studies should involve the definition of the extent and severity of methylnaphthalene toxicity after single dose exposures with attention to both the nasal and respiratory epithelia. The cytochromes P450 responsible for the initial activation of these agents in rodents with subsequent complimentary studies in primate models should help determine whether key metabolic processes responsible for toxicity occur also in primates. Finally, the precise involvement of reactive metabolite formation and adduction of cellular proteins in toxicity will be important in not only assessing the potential for human toxicity, but also in developing an understanding of the genetic and environmental factors which could alter the toxicity of these agents.

  • Identification of proteins adducted by reactive metabolites of naphthalene and 1-Nitronaphthalene in dissected airways of rhesus macaques.
    Proteomics, 2006
    Co-Authors: Ching Yu Lin, Dexter Morin, Charles G. Plopper, Bridget C. Boland, Lisa A. Miller, Young Jin Lee, Michelle Salemi, Alan R. Buckpitt
    Abstract:

    Naphthalene and 1-Nitronaphthalene are ambient air pollutants, which undergo P450-dependent bioactivation in the lung. Reactive metabolites of naphthalene and 1-Nitronaphthalene covalently bind to proteins, and the formation of covalent adducts correlates with airway epithelial cell injury in rodent models. These studies were designed to identify protein adducts generated from these reactive metabolites within distal respiratory airways. Distal bronchioles and parenchyma from rhesus monkeys were incubated with [(14)C]naphthalene or [(14)C]1-Nitronaphthalene. Proteins were separated by 2-DE, blotted to PVDF membranes, and adducted proteins imaged by storage phosphor analysis. MS of in-gel tryptic digests identified numerous adducted proteins including: eight cytoskeletal proteins, two chaperone proteins, seven metabolic enzymes, one redox protein, two proteins involved in ion balance and cell signaling, and two extracellular proteins. While many proteins are adducted by both naphthalene and 1-Nitronaphthalene, some are unique to the individual toxicant and airway subcompartment. Although the role which adduction of these proteins plays in cytotoxicity was not evaluated, these studies provide candidate proteins for future work designed to determine the importance of protein adducts in the mechanisms of toxicity and for developing biomarkers useful in determining the relevance of findings in animal models to exposed human populations.

  • Site-Specific Metabolism of Naphthalene and 1-Nitronaphthalene in Dissected Airways of Rhesus Macaques
    The Journal of pharmacology and experimental therapeutics, 2004
    Co-Authors: Bridget C. Boland, Ching Yu Lin, Dexter Morin, Charles G. Plopper, Lisa A. Miller, Alan R. Buckpitt
    Abstract:

    Studies in rodents have demonstrated the importance of cytochrome P450 monooxygenases in generating reactive metabolites that produce Clara cell injury. Pulmonary P450 activities in rodents are much higher than those in primates, raising the issue of relevance of rodent data to primates. Few studies on P450-catalyzed activation of cytotoxicants in subcompartments of primate lung have been reported. Accordingly, infant monkey airway subcompartments, including trachea, proximal, midlevel, distal airways, and parenchyma, were incubated with naphthalene or 1-Nitronaphthalene to define metabolism at both high (500 microM) and low (50 microM) substrate concentrations. There was a relatively even distribution of metabolizing activities for naphthalene across subcompartments, but at high concentrations of 1-Nitronaphthalene, lower airways (midlevel airway through parenchyma) showed higher bioactivation than upper airways. Dihydrodiol was the predominant water-soluble metabolite of naphthalene generated by all subcompartments, whereas covalently bound metabolites accounted for the greatest percentage of 1-Nitronaphthalene metabolites, especially in lower airways. As anticipated, the amounts of metabolite covalently bound as a percentage of total metabolite formed increased dramatically with the 10-fold increase in substrate concentration. With both substrates, the formation of water-soluble metabolites was approximately 100 times less than observed previously in rodents. We conclude that 1) there are significant quantitative differences between rhesus and rodents in substrate bioactivation; 2) the distribution of metabolizing activities for naphthalene but not 1-Nitronaphthalene is significantly different for rodents and primates; and 3) a very high percentage of the metabolites generated, particularly for 1-Nitronaphthalene, is bound covalently to cellular proteins.