TY - JOUR AU - Eytcheson, S.A.* AU - Tetko, I.V. C1 - 75321 C2 - 57935 CY - 1155 16th St, Nw, Washington, Dc 20036 Usa SP - 1443-1451 TI - Which modern AI methods provide accurate predictions of toxicological end points? Analysis of Tox24 challenge results. JO - Chem. Res. Toxicol. VL - 38 IS - 9 PB - Amer Chemical Soc PY - 2025 SN - 0893-228X ER - TY - JOUR AU - Roncaglioni, A.* AU - Kovarich, S.* AU - Mansouri, K.* AU - Tetko, I.V. C1 - 75322 C2 - 57936 SP - 1281-1282 TI - Advancing human and environmental safety science using In Silico methods. JO - Chem. Res. Toxicol. VL - 38 IS - 8 PY - 2025 SN - 0893-228X ER - TY - JOUR AU - Sturla, S.* AU - Dai, J.* AU - Kraegeloh, A.* AU - Normura, D.* AU - Tetko, I.V. AU - Wang, Y.* AU - Serrano, J.* C1 - 72981 C2 - 56762 SP - 127-128 TI - Invitation to apply or nominate for membership in the early career board of Chemical Research in Toxicology. JO - Chem. Res. Toxicol. VL - 37 IS - 2 PY - 2024 SN - 0893-228X ER - TY - JOUR AU - Tetko, I.V. C1 - 70720 C2 - 55555 CY - 1155 16th St, Nw, Washington, Dc 20036 Usa SP - 825-826 TI - Tox24 Challenge. JO - Chem. Res. Toxicol. VL - 37 IS - 6 PB - Amer Chemical Soc PY - 2024 SN - 0893-228X ER - TY - JOUR AU - Klambauer, G.* AU - Clevert, D.A.* AU - Shah, I.* AU - Benfenati, E.* AU - Tetko, I.V. C1 - 67984 C2 - 54462 SP - 1163-1167 TI - Introduction to the special issue: AI meets toxicology. JO - Chem. Res. Toxicol. VL - 36 IS - 8 PY - 2023 SN - 0893-228X ER - TY - JOUR AU - Tetko, I.V. AU - Klambauer, G.* AU - Clevert, D.A.* AU - Shah, I.* AU - Benfenati, E.* C1 - 66013 C2 - 53054 SP - 1289-1290 TI - Artificial intelligence meets toxicology. JO - Chem. Res. Toxicol. VL - 35 IS - 8 PY - 2022 SN - 0893-228X ER - TY - JOUR AU - Kleinstreuer, N.C.* AU - Tetko, I.V. AU - Tong, W.* C1 - 63509 C2 - 51345 SP - 171-175 TI - Introduction to special issue: Computational toxicology. JO - Chem. Res. Toxicol. VL - 34 IS - 2 PY - 2021 SN - 0893-228X ER - TY - JOUR AB - Widespread smoke from wildfires and biomass burning contributes to air pollution and the deterioration of air quality and human health. A common and major emission of biomass burning, often found in collected smoke particles, is spherical wood tar particles, also known as "tar balls". However, the toxicity of wood tar particles and the mechanisms that govern their health impacts and the impact of their complicated chemical matrix are not fully elucidated. To address these questions, we generated wood tar material from wood pyrolysis and isolated two main subfractions: water-soluble and organic-soluble fractions. The chemical characteristics as well as the cytotoxicity, oxidative damage, and DNA damage mechanisms were investigated after exposure of A549 and BEAS-2B lung epithelial cells to wood tar. Our results suggest that both wood tar subfractions reduce cell viability in exposed lung cells; however, these fractions have different modes of action that are related to their physicochemical properties. Exposure to the water-soluble wood tar fraction increased total reactive oxygen species production in the cells, decreased mitochondrial membrane potential (MMP), and induced oxidative damage and cell death, probably through apoptosis. Exposure to the organic-soluble fraction increased superoxide anion production, with a sharp decrease in MMP. DNA damage is a significant process that may explain the course of toxicity of the organic-soluble fraction. For both subfractions, exposure caused cell cycle alterations in the G2/M phase that were induced by upregulation of p21 and p16. Collectively, both subfractions of wood tar are toxic. The water-soluble fraction contains chemicals (such as phenolic compounds) that induce a strong oxidative stress response and penetrate living cells more easily. The organic-soluble fraction contained more polycyclic aromatic hydrocarbons (PAHs) and oxygenated PAHs and induced genotoxic processes, such as DNA damage. AU - Pardo, M.* AU - Li, C.* AU - Fang, Z.* AU - Levin-Zaidman, S.* AU - Dezorella, N.* AU - Czech, H. AU - Martens, P.* AU - Käfer, U.* AU - Gröger, T.M. AU - Rüger, C.P.* AU - Friederici, L.* AU - Zimmermann, R. AU - Rudich, Y.* C1 - 62071 C2 - 50612 CY - 1155 16th St, Nw, Washington, Dc 20036 Usa SP - 1588-1603 TI - Toxicity of water- and organic-soluble wood tar fractions from biomass burning in lung epithelial cells. JO - Chem. Res. Toxicol. VL - 34 IS - 6 PB - Amer Chemical Soc PY - 2021 SN - 0893-228X ER - TY - JOUR AB - Selecting a model in predictive toxicology often involves a trade-off between prediction performance and explainability: should we sacrifice the model performance to gain explainability or vice versa. Here we present a comprehensive study to assess algorithm and feature influences on model performance in chemical toxicity research. We conducted over 5000 models for a Tox21 bioassay data set of 65 assays and ∼7600 compounds. Seven molecular representations as features and 12 modeling approaches varying in complexity and explainability were employed to systematically investigate the impact of various factors on model performance and explainability. We demonstrated that end points dictated a model's performance, regardless of the chosen modeling approach including deep learning and chemical features. Overall, more complex models such as (LS-)SVM and Random Forest performed marginally better than simpler models such as linear regression and KNN in the presented Tox21 data analysis. Since a simpler model with acceptable performance often also is easy to interpret for the Tox21 data set, it clearly was the preferred choice due to its better explainability. Given that each data set had its own error structure both for dependent and independent variables, we strongly recommend that it is important to conduct a systematic study with a broad range of model complexity and feature explainability to identify model balancing its predictivity and explainability. AU - Wu, L.* AU - Huang, R.* AU - Tetko, I.V. AU - Xia, Z. AU - Xu, J.* AU - Tong, W.* C1 - 61199 C2 - 50085 CY - 1155 16th St, Nw, Washington, Dc 20036 Usa SP - 541-549 TI - Trade off predictivity and explainability for machine-learning powered predictive toxicology: An in-depth investigation with Tox21 data sets. JO - Chem. Res. Toxicol. VL - 34 IS - 2 PB - Amer Chemical Soc PY - 2021 SN - 0893-228X ER - TY - JOUR AU - Kleinstreuer, N.C.* AU - Tong, W.* AU - Tetko, I.V. C1 - 58694 C2 - 48280 SP - 687-688 TI - Computational toxicology. JO - Chem. Res. Toxicol. VL - 33 IS - 3 PY - 2020 SN - 0893-228X ER - TY - JOUR AB - Particulate matter (PM), an important component of air pollution, induces significant adverse health effects. Many of the observed health effects caused by inhaled PM are associated with oxidative stress and inflammation. This association has been linked in particular to the particles' chemical components, especially the inorganic/metal and the organic/polycyclic aromatic hydrocarbon (PAH) fractions, and their ability to generate reactive oxygen species in biological systems. The transcription factor NF-E2 nuclear factor erythroid-related factor 2 (Nrf2) is activated by redox imbalance and regulates the expression of phase II detoxifying enzymes. Nrf2 plays a key role in preventing PM-induced toxicity by protecting against oxidative damage and inflammation. This review focuses on specific PM fractions, particularly the dissolved metals and PAH fractions, and their roles in inducing oxidative stress and inflammation in cell and animal models with respect to Nrf2 and mitochondria. AU - Pardo, M.* AU - Qiu, X.* AU - Zimmermann, R. AU - Rudich, Y.* C1 - 59001 C2 - 48520 SP - 1110-1120 TI - Particulate matter toxicity is Nrf2 and mitochondria dependent: The roles of metals and polycyclic aromatic hydrocarbons. JO - Chem. Res. Toxicol. VL - 33 IS - 5 PY - 2020 SN - 0893-228X ER - TY - JOUR AB - The ToxCast EPA challenge was managed by TopCoder in Spring 2014. The goal of the challenge was to develop a model to predict the lowest effect level (LEL) concentration based on in vitro measurements and calculated in silico descriptors. This article summarizes the computational steps used to develop the Rank-I model, which calculated the lowest prediction error for the secret test data set of the challenge. The model was developed using the publicly available Online CHEmical database and Modeling environment (OCHEM), and it is freely available at http://ochem.eu/article/68104 . Surprisingly, this model does not use any in vitro measurements. The logic of the decision steps used to develop the model and the reason to skip inclusion of in vitro measurements is described. We also show that inclusion of in vitro assays would not improve the accuracy of the model. AU - Novotarskyi, S.* AU - Abdelaziz, A.* AU - Sushko, Y.* AU - Körner, R.* AU - Vogt, J.* AU - Tetko, I.V. C1 - 48651 C2 - 41248 CY - Washington SP - 768-775 TI - ToxCast EPA in vitro to in vivo challenge: Insight into the rank-I model. JO - Chem. Res. Toxicol. VL - 29 IS - 5 PB - Amer Chemical Soc PY - 2016 SN - 0893-228X ER - TY - JOUR AB - Occupational and environmental exposure to increased concentrations of Manganese (Mn) can lead to an accumulation of this element in the brain. The consequence is an irreversible damage of dopaminergic neurons leading to a disease called manganism with a clinical presentation similar to the one observed in Parkinson´s Disease. Human as well as animal studies indicate that Mn is mainly bound to low molecular mass (LMM) compounds such as Mn-citrate when crossing neural barriers. The shift towards LMM compounds might already take place in serum due to elevated Mn concentrations in the body.In this study we investigated Mn-species pattern in serum in two different animal models by size exclusion chromatography-inductively coupled plasma mass spectrometry (SEC-ICP-MS). A subchronic feeding of rats with elevated levels of Mn led to an increase in LMM compounds, mainly Mn-citrate and Mn bound to amino acids. In addition, a single i.v. injection of Mn showed an increase in Mn-transferrin and Mn bound to amino acids one hour after injection, while species values were rebalanced four days after the injection. Results from Mn-speciation were correlated to the brain metabolome determined by means of electrospray ionization ion cyclotron resonance Fourier transform mass spectrometry (ESI-ICR/FT-MS). The powerful combination of Mn-speciation in serum with metabolomics of the brain underlined the need for Mn-speciation in exposure scenarios instead of determination of whole Mn concentrations in blood. The progress of Mn-induced neuronal inflammation might therefore be assessed on basis of known serum Mn-species. AU - Neth, K. AU - Lucio, M. AU - Walker, A. AU - Kanawati, B. AU - Zorn, J. AU - Schmitt-Kopplin, P. AU - Michalke, B. C1 - 45075 C2 - 37196 CY - Washington SP - 1434-1442 TI - Diverse serum manganese species affect brain metabolites depending on exposure conditions. JO - Chem. Res. Toxicol. VL - 28 IS - 7 PB - Amer Chemical Soc PY - 2015 SN - 0893-228X ER - TY - JOUR AB - The critical importance of glutathione in mitigating the deleterious effects of electrophile generating drugs such as acetaminophen (APAP) is well established. However, the role of other antioxidant systems, such as that provided by thioredoxin, has not been extensively studied. Selenoprotein thioredoxin reductase 1 (Txnrd1) is important for attenuating activation of the apoptosis signaling-regulating kinase 1 (ASK1) and the c-Jun N-terminal kinase (JNK) pathway caused by high doses of APAP. Therefore, a detailed investigation of the role of Txnrd1 in APAP-induced hepatotoxicity was conducted. Liver-specific Txnrd1 knockout mice (Txnrd1(ΔLiv)) were generated and treated with a hepatotoxic dose (400 mg/kg) of APAP for 1 or 6 h. Liver toxicity was assessed by measuring the activities of liver enzymes aspartate aminotransferase and alanine aminotransferase in serum, in addition to histopathological analysis of liver sections and analysis of glutathione levels. At 1 h post-APAP treatment, total and mitochondrial glutathione levels in control and Txnrd1(ΔLiv) mice were similarly depleted. However, at 6 h post-APAP treatment, Txnrd1(ΔLiv) mice were resistant to APAP toxicity as liver enzymes and histology were not significantly different from the corresponding untreated mice. Analyses revealed the compensatory up-regulation of many of the nuclear factor erythroid 2-related factor 2 (NRF2) target genes and proteins in Txnrd1(ΔLiv) mice with and without APAP treatment. Yet, JNK was phosphorylated to a similar extent in APAP-treated control mice. The results suggest that Txnrd1(ΔLiv) mice are primed for xenobiotic detoxication primarily through NRF2 activation. AU - Patterson, A.D.* AU - Carlson, B.A.* AU - Li, F.* AU - Bonzo, J.A.* AU - Yoo, M.H.* AU - Krausz, K.W.* AU - Conrad, M. AU - Chen, C.* AU - Gonzalez, F.J.* AU - Hatfield, D.L.* C1 - 26050 C2 - 32044 SP - 1088-1096 TI - Disruption of thioredoxin reductase 1 protects mice from acute acetaminophen-induced hepatotoxicity through enhanced NRF2 activity. JO - Chem. Res. Toxicol. VL - 26 IS - 7 PB - Amer. Chemical Soc. PY - 2013 SN - 0893-228X ER - TY - JOUR AB - 1,3-Butadiene (BD) is a Class 1 carcinogen present at workplaces, in polluted air, in automobile exhaust, and in tobacco smoke. 2-Hydroxybutene-1-yl mercapturic acid (2-MHBMA) is a urinary metabolite often measured as a biomarker for exposure to BD. Here, we show for the first time that an additional MHBMA isomer is present at significant amounts in human urine, 1-hydroxybutene-2-yl mercapturic acid (1-MHBMA). For its quantification, a highly sensitive UPLC-HILIC-MS/MS method was developed and validated. Analyzing urinary samples of 183 volunteers, we demonstrate that 1-MHBMA is a novel and potentially more reliable biomarker for BD exposure than the commonly analyzed 2-MHBMA. AU - Sterz, K.* AU - Scherer, G.* AU - Krumsiek, J. AU - Theis, F.J. AU - Ecker, J.* C1 - 8577 C2 - 30190 SP - 1565-1567 TI - Identification and quantification of 1-hydroxybutene-2-yl mercapturic acid in human urine by UPLC- HILIC-MS/MS as a novel biomarker for 1,3-butadiene exposure. JO - Chem. Res. Toxicol. VL - 25 IS - 8 PB - Amer. Chemical Soc. PY - 2012 SN - 0893-228X ER - TY - JOUR AB - no Abstract AU - Wittmaack, K. C1 - 7126 C2 - 29512 SP - 7-10 TI - Reply to the letter to the editor regarding my article on dose metrics in nanotoxicity studies (Wittmaack, 2011). JO - Chem. Res. Toxicol. VL - 25 IS - 1 PB - American Chemical Society PY - 2012 SN - 0893-228X ER - TY - JOUR AB - This study aimed at identifying the dose metric applicable to studies on the viability of cells exposed to nanoparticles (NPs) in vitro. A previously reported set of data was evaluated very carefully. The extent of cell death after 24-h exposure of three cell lines to suspended silica NPs (<30 nm) was quantified using four different viability/cytotoxicity assays. Data on NP uptake in cells after 6-h exposure were also reported. Evidence is provided that, in spite of the small size of the NPs, mass transport to the cells cannot be explained solely by diffusion. Gravitational settling must have contributed significantly, presumably as the result of the formation of large agglomerates. Appropriately adjusted response data, with typically 22 combinations of mass concentration and height of the medium for each cell line, could be integrated in universal diagrams, provided the dose was quoted in terms of the areal density of NP mass delivered to the cells. Loss of viability became observable only if cells were exposed to the equivalent of 1 to 5 closely packed layers of NPs; the dose required for complete cell death ranged between 4 and about 20 layers of NPs. The results suggest that the cell-death phenomena observed in the evaluated work and in many similar studies reported in the literature constitute a matter of cell overload with nanostructured matter. This finding also implies that the toxic potential of individual silicate NPs is very low. Strategies for the design of advanced future work are outlined. AU - Wittmaack, K. C1 - 5606 C2 - 28534 SP - 150-158 TI - Novel dose metric for apparent cytotoxicity effects generated by in vitro cell exposure to silica nanoparticles. JO - Chem. Res. Toxicol. VL - 24 IS - 2 PB - Amer Chemical Soc PY - 2011 SN - 0893-228X ER - TY - JOUR AB - Soft single photon ionization (SPI)-time-of-flight mass spectrometry (TOFMS) has been applied for the quantitative puff-by-puff-resolved characterization of selected toxic species in cigarette mainstream smoke, namely, nitric oxide (NO), acetaldehyde, butadiene, acetone, isoprene, benzene, toluene, ethyl benzene, and xylene. The 2R4F research cigarette was investigated for whole smoke (unfiltered) and gas phase (filtered). It has been demonstrated that the existing smoking regime for total smoke analysis (smoke from a complete cigarette) features deficiencies when applied to puff-resolved measurements. This is especially the case for analysis in which a glass fiber filter is used to separate the smoke particulate and gas phases because material is desorbed from the filter and influences succeeding puffs. Regarding whole smoke measurements, succeeding puffs are affected by contamination and memory effects of the smoking machine itself, but to a lower extent. Quantitative puff-resolved smoke profiles show that the puff yields of the various constituents can differ tremendously. Most species' concentrations increase gradually with puff number, which is mainly due to the reduction in length of the cigarette. However, high yields in the first puff are observed for butadiene and isoprene, suggesting different formation mechanisms for these compounds. First results are presented in which these high yields in the first puff are mainly associated with the gaseous fraction of the smoke. AU - Adam, T.* AU - Mitschke, S.* AU - Streibel, T. AU - Baker, R.R.* AU - Zimmermann, R. C1 - 1277 C2 - 23738 SP - 511-520 TI - Quantitative puff-by-puff-resolved characterization of selected toxic compounds in cigarette mainstream smoke. JO - Chem. Res. Toxicol. VL - 19 IS - 4 PY - 2006 SN - 0893-228X ER - TY - JOUR AB - d-Serine is nephrotoxic in rats. Based on circumstantial evidence, it has been suspected that d-amino-acid oxidase is involved in this nephrotoxicity. Since we found that LEA/SENDAI rats lacked d-amino-acid oxidase, we examined whether this enzyme was associated with d-serine-induced nephrotoxicity using the LEA/SENDAI rats and control F344 rats. When d-propargylglycine, which is known to have a nephrotoxic effect through its metabolism by d-amino-acid oxidase, was injected intraperitoneally into the F344 rats, it caused glucosuria and polyuria. However, injection of d-propargylglycine into LEA/SENDAI rats did not cause any glucosuria or polyuria, indicating that d-amino-acid oxidase is definitely not functional in these rats. d-Serine was then injected into the F344 and LEA/SENDAI rats. It caused glucosuria and polyuria in the F344 rats but not in the LEA/SENDAI rats. These results indicate clearly that d-amino-acid oxidase is responsible for the d-serine-induced nephrotoxicity. AU - Maekawa, M.* AU - Okamura, T.* AU - Kasai, N.* AU - Hori, Y.* AU - Summer, K.H. AU - Konno, R.* C1 - 1310 C2 - 23380 SP - 1678-1682 TI - D-Amino-acid Oxidase Is Involved in D-Serine-Induced Nephrotoxicity. JO - Chem. Res. Toxicol. VL - 18 IS - 11 PY - 2005 SN - 0893-228X ER - TY - JOUR AB - Metabolic activation, DNA binding, and tumorigenicity of the carcinogenic polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene (DB[a,l]P) catalyzed by murine cytochrome P450 (P450) enzymes were investigated. DNA binding of DB[a,l]P in human mammary carcinoma MCF-7 and human P450-expressing Chinese hamster V79 cell lines was previously shown to occur preferentially with metabolically generated fjord region DB[a,l]P-11,12-dihydrodiol 13,14-epoxides (DB[a,l]PDE). To elucidate different capabilities of murine P450 1A1 and 1B1 for metabolic activation of DB[a,l]P, V79 cell cultures stably expressing P450s 1A1 or 1B1 from mice were exposed to 10 or 100 nM DB[a,l]P. Both cell lines transformed DB[a,l]P to DNA binding intermediates. As with V79 cells expressing the corresponding human P450 enzyme [Luch et al. (1998) Chem. Res. Toxicol. 11, 686−695], murine P450 1B1-catalyzed metabolism and DNA binding proceeded exclusively through generation of fjord region DB[a,l]PDE. In addition, only DB[a,l]PDE-derived DNA adducts were found in V79 cells expressing P450 1A1 from mice. This is in contrast to our recent findings with V79 cells expressing P450 1A1 from humans or rats which catalyzed the formation of both highly polar DNA adducts as well as nonpolar DB[a,l]PDE-DNA adducts. To establish the role of P450 1B1 in DB[a,l]P-induced tumor formation in vivo, we treated P450 1B1-null and wild-type mice intragastrically and monitored survival rates and appearance of neoplasias in various organs. All wild-type mice (n = 17) used in this study developed at least one tumor at one site (tumor rate of 100%). In contrast, 5 of 13 P450 1B1-null mice were observed to be free from any tumor (tumor rate of 62%). The organ sites of tumor formation and the dignity of tumors were different between wild-type and P450 1B1-null mice. Wild-type mice were diagnosed with both benign and malignant tumors of the ovaries, lymphoid tissues, as well as with skin and endometrial hyperplasias, whereas P450 1B1-null mice developed only lung adenomas and endometrial hyperplasias. DNA binding studies using embryonic fibroblasts isolated from these animals provided further evidence that P450 1B1-catalyzed formation of fjord region DB[a,l]PDE-DNA adducts is the critical step in DB[a,l]P-mediated carcinogenesis in mice, and probably also in man. AU - Buters, J.T.M.* AU - Mahadevan, B.* AU - Quintanilla-Martinez, L. AU - Gonzales, F.J.* AU - Greim, H.* AU - Baird, W.M.* AU - Luch, A.* C1 - 21952 C2 - 20470 SP - 1127-1135 TI - Cytochrome P450 1B1 Determines Susceptibility to Dibenzo[a,l]pyrene-Induced Tumor Formation. JO - Chem. Res. Toxicol. VL - 15 IS - 9 PY - 2002 SN - 0893-228X ER - TY - JOUR AB - Bisphenol A is a widely used industrial chemical with many potential sources of human exposure. Bisphenol A is a weak estrogen and has been implicated as an endocrine disruptor". This term is used for a variety of chemicals encountered in the environment which have estrogenic activity. It has been postulated that human exposure to these chemicals may elicit unwanted estrogenic effects in humans such as reduced fertility, altered development and cancer. Up to now the body burden of bisphenol A in humans is unknown. Therefore, we investigated the metabolism and toxicokinetics of bisphenol A in humans exposed to low doses since systemic bioavailability has a major influence on possible estrogenic effects in vivo. Human subjects (three males and three females, and four males for detailed description of blood kinetics) were administered d(16)-bisphenol A (5 mg). Blood and urine samples were taken in intervals (up to 96 h), metabolites formed were identified by GC/MS and LC-MS/MS and quantified by GC/MS-NCI and LC-MS/MS. d(16)-Bisphenol A glucuronide was the only metabolite of d(16)-bisphenol A detected in urine and blood samples, and concentrations of free d(16)-bisphenol A were below the limit of detection both in urine (6 nM) and blood samples (10 nM). d(16)-Bisphenol A glucuronide was cleared from human blood and excreted with urine with terminal half-lives of less than 6 h; the applied doses were completely recovered in urine as d(16)-bisphenol A glucuronide. Maximum blood levels of d(16)-bisphenol A glucuronide (similar to800 nM) were measured 80 min after oral administration of d(16)-bisphenol A (5 mg). The obtained data indicate major species differences in the disposition of bisphenol A. Enterohepatic circulation of bisphenol A glucuronide in rats results in a slow rate of excretion, whereas bisphenol A is rapidly conjugated and excreted by humans due to the absence of enterohepatic circulation. The efficient glucuronidation of bisphenol A and the rapid excretion of the formed glucuronide result in a low body burden of the estrogenic bisphenol A in humans following oral absorption of low doses." AU - Völkel, W.* AU - Colnot, Th.* AU - Csanády, G.A. AU - Filser, J.G. AU - Dekant, W.* C1 - 10300 C2 - 20383 SP - 1281-1287 TI - Metabolism and Kinetics of Bisphenol A in Humans at Low Doses Following Oral Administration. JO - Chem. Res. Toxicol. VL - 15 IS - 10 PB - Society PY - 2002 SN - 0893-228X ER - TY - JOUR AB - Metabolic activation of the strongly carcinogenic polycyclic aromatic hydrocarbon (PAH) dibenzo[a,l]pyrene (DB[a,l]P) and its trans-8,9-dihydrodiol (trans-8,9-diol) catalyzed by human cytochromes P450 (P450) 1A1 and 1B1 was investigated. DNA binding of DB[a,l]P in mammalian cell lines has previously been shown to be preferentially mediated by fjord region DB[a,l]P-11,12-dihydrodiol 13,14-epoxides (DB[a,l]PDE). In order to elucidate different capabilities of both P450 enzymes for metabolic activation of DB[a, l]P V79 Chinese hamster cells, stably expressing human P450s 1A1 or 1B1 have been exposed to the parent PAH or its racemic trans-8, 9-diol. For this purpose, synthesis and spectroscopic characterization of the trans-DB[a,l]P-8,9-diol and its individual enantiomers have been achieved. Both human P450-expressing cell lines were capable of transforming DB[a,l]P to its fjord region DB[a, l]PDE, but the extent of metabolism to DB[a,l]PDE catalyzed by human P450 1B1 was higher compared to human P450 1A1 at all times measured. On the other hand, cytotoxicity studies performed with the same incubation systems emerged stronger effects by DB[a,l]P and its enantiomeric trans-11,12-diols in human P450 1A1-expressing cells. Both human P450 enzymes stereospecifically catalyzed the formation of the (-)-DB[a,l]P-11,12-diol with R,R-configuration, whereas only the human P450 1A1-expressing cells form small amounts of the K-region trans-8,9-diol with high excess of the (+)-(8R, 9R)-enantiomer. Application of trans-DB[a,l]P-8,9-diol in metabolism studies revealed that this compound is converted by human P450s 1A1 and 1B1 to several diol phenols and bis-diols. However, and even at concentrations as high as 10 microM, in both cell lines the trans-DB[a,l]P-8,9-diol showed no cytotoxicity at all, suggesting that an activation of DB[a,l]P via further oxidation of the K-region trans-8,9-diol plays a minor role. AU - Luch, A.* AU - Schober, W.* AU - Soballa, V.J.* AU - Raab, G.* AU - Greim, H. AU - Jacob, J.* AU - Doehmer, J.* AU - Seidel, A.* C1 - 23987 C2 - 31428 SP - 353-364 TI - Metabolic activation of dibenzo[a,l]pyrene by human cytochrome P450 1A1 and P450 1B1 expressed in V79 Chinese hamster cells. JO - Chem. Res. Toxicol. VL - 12 IS - 4 PB - Amer. Chemical Soc. PY - 1999 SN - 0893-228X ER - TY - JOUR AB - The chemistry of the nonenzymatic oxidation of the rat liver carcinogen, 2-nitropropane, and its anionic form, propane-2-nitronate, was investigated using pulse radiolysis and EPR/spin trapping with 3,5-dibromo-4-nitrosobenzenesulfonic acid as the trapping agent. The results suggest that, following initial oxidation to a secondary alkyl radical, propane-2-nitronate is effectively degraded in a peroxidative chain reaction with the intermediary formation of peroxyl and NO2.radicals. The latter radical was shown to react appreciably fast with ribonucleosides, deoxyribonucleosides, and guanosine nucleotides. It is proposed that nonenzymatic formation of NO2.radicals after enzymatic oxidation of propane-2-nitronate to the corresponding secondary alkyl radical accounts for the induction of DNA damage observed after exposure of rats to 2-nitropropane. AU - Bors, W. AU - Michel, C. AU - Dalke, C. AU - Stettmaier, K. AU - Saran, M. AU - Andrae, U. C1 - 20152 C2 - 13329 SP - 302-309 TI - Radical Intermediates during the Oxidation of Nitropropanes. The Formation of NO2 from 2- Nitropropane, Its Reactivity with Nucleosides, and Implications for the Genotoxicity of 2- Nitropropane. JO - Chem. Res. Toxicol. VL - 6 IS - 3 PY - 1993 SN - 0893-228X ER - TY - JOUR AB -   The chemistry of the nonenzymatic oxidation of the rat liver carcinogen, 2-nitropropane, and its anionic form, propane-2-nitronate, was investigated using pulse radiolysis and EPR/spin trapping with 3,5-dibromo-4-nitrosobenzenesulfonic acid as the trapping agent. The results suggest that, following initial oxidation to a secondary alkyl radical, propane-2-nitronate is effectively degraded in a peroxidative chain reaction with the intermediary formation of peroxyl and NO2.radicals. The latter radical was shown to react appreciably fast with ribonucleosides, deoxyribonucleosides, and guanosine nucleotides. It is proposed that nonenzymatic formation of NO2.radicals after enzymatic oxidation of propane-2-nitronate to the corresponding secondary alkyl radical accounts for the induction of DNA damage observed after exposure of rats to 2-nitropropane.   AU - Bors, W. AU - Michel, C. AU - Dalke, C. AU - Stettmaier, K. AU - Saran, M. AU - Andrae, U. C1 - 40339 C2 - 40082 SP - 302-309 TI - Radical intermediates during the oxidation of nitropropanes. The formation of NO2 from 2-nitropropane, its reactivity with nucleosides, and implications for the genotoxicity of 2-nitropropane. JO - Chem. Res. Toxicol. VL - 6 IS - 3 PY - 1993 SN - 0893-228X ER -