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Metabolism and Toxicity of Occupational Neurotoxicants: Genetic, Physiological, and Environmental Determinants
Published in Lucio G. Costa, Luigi Manzo, Occupatinal Neurotoxicology, 2020
Stefano M. Candura, Luigi Manzo, Anna F. Castoldi, Lucio G. Costa
PAH such as benzo(a)pirene and 3-methylcholantrene are environmental pollutants formed by incomplete combustion of organic matter. Besides being formed in food during cooking, they can be found in the exhaust gases generated by vehicle engines, industrial plants, domestic heating appliances, and tobacco smoke.80 PAH appear to induce selectively few specific forms of cytochromes P450, namely CYP1 Al and CYP1A2. The molecular mechanism responsible for CYP1A1 induction involves PAH interaction with a cytosolic receptor, denoted as the Ah receptor. The PAH-receptor complex then is translocated into the nucleus, where it causes selective transcriptional gene activation resulting in de novo synthesis of enzymes. In addition to benzo(a)pirene and 3-methylcholantrene, chemicals which bind to the Ah receptor include 2,3,7,8-tetrachloro-dibenzo-/?-dioxin (TCDD), benzo(a)anthracene and β-naphtoflavone.77,78
Mechanisms of chemically induced respiratory toxicities
Published in Philippe Camus, Edward C Rosenow, Drug-induced and Iatrogenic Respiratory Disease, 2010
CYP1A1 is a P450 enzyme that is involved in the metabolism of a wide variety of polycyclic aromatic compounds. It is absent or present at minimal levels in the lungs of rodents, but is highly induced after treatment with agents such as 3-methylcholanthrene or 2,3,7,8-tetrachlorodibenzodioxin (dioxin).24–26 In rabbits and rats, the induced P450 is expressed in the Clara cells, Type II cells and endothelial cells. In mice, this P450 is induced in the Type II and endothelial cells, but is not induced in the Clara cells, indicating a species difference. In humans, CYP1A1 is highly induced by cigarette smoke.27,28
Evaluation of potential toxicity of smoke from controlled burns of furnished rooms – effect of flame retardancy
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Thomas G. Osimitz, Wiebke Droege, Giel Hendriks, Matthew S. Blais
The ability of the same test articles to activate human AhR was determined using a human AhR reporter assay system with a commercial reporter cell line (Indigo Biosciences) in which luciferase is expressed from an AhR-dependent transgene in an AhR activation system. (3E)-6-Bromo-3-[3-(hydroxyamino)indol-2-ylidene]-1-methylindol-2-one (MeBio) was the positive control. The binding of AhR is an essential step in a pathway that includes the translocation of the ligand-receptor complex into the nucleus of the cell, dimerization of the AhR with the AhR nuclear translocator (ARNT) protein, and binding of the ligand:AhR:ARNT complex to the corresponding DNA recognition sequence. The result is transcription and translation of expression of multiple genes, most noteworthy for cytochrome P4501A1 (CYP1A1). All dioxin-like compounds are assumed to act through this AhR signal transduction pathway (Birnbaum 1994; Safe 1990). Among the toxicological effects associated with AhR activation are chronic adverse health effects, including cancer, cardiovascular disease, chronic kidney disease, immunotoxicity, and reproductive disorders (Larsson et al. 2018; Zhao et al. 2019). The AhR signaling pathway also cross talks with the estrogen receptor pathway suggesting that AhR-activating compounds may induce estrogen-like endocrine effects (Larsson et al. 2018). Besides screening chemicals for potential toxicity, Larsson et al. (2018) noted that the AhR assay is used to measure levels of PAHs in samples of sediments and water, blood plasma, sewage sludge, and food.
Genotoxic effect induced by dried nicotiana tabacum leaves from tobacco barns (kiln-houses) in chinese hamster lung fibroblast cells (V79)
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Daiana Dalberto, Caroline Cardoso Nicolau, Melissa Rosa De Sousa, Ana Letícia Hilário Garcia, Fernanda Boaretto, Jaqueline Nascimento Picada, Guilherme Maurício Soares De Souza, Paola Chytry, Johnny Ferraz Dias, Cleverson Costa Feistel, Alexandre Barros Falcão Ferraz, Ivana Grivicich, Juliana Da Silva
Thus, Systems biology approach was used to elucidate the human biological processes related to mixture of compounds detected in the dry tobacco leaves (inorganic elements and nicotine). The major HBidentified in the network were the proteins AKT1, PPP2R1A, CREBBP, CYP1A1, EP300, PPP2CA, HSP90AA1, and CDC5L. Kahl, Da Silva, and Da Silva (2016) showed the presence of AKT1, CREBBP, and CYP1A1 and related to the effect of nicotine and pesticides on telomere length in tobacco farmers. The AKT1 protein was the one that stood out in the centrality graph. According to data found on genetic cards, this protein regulates a wide variety of cellular functions, such as cell stem cell manutention, proliferation, metabolism, and angiogenesis in normal and malignant cells (Miricescu et al. 2019). A diverse set of cascades have been implicated in various cancers including those mediated by serine/threonine kinases such AKT/PP2CA (Ruvolo 2016). CREBBP protein and its homologue EP300 are transcriptional co-activators of different transcription factors that are involved in a wide array of cellular activities, such as DNA repair, and are related with respiratory epithelium tumorigenesis (Karamouzis, Konstantinopoulos, and Papavassiliou 2007). Another gene that stands out in the centrality analysis was the CYP1A1 gene, which can metabolize a broad range of foreign compounds and drugs. CYP1A1 is important in defining the efficacy and toxicity/carcinogenicity of drugs and foreign compounds. Unlike other CYP enzymes, CYP1A1 is found predominantly in liver tissue and to a lesser extent lung. CYP1A1is involved in the metabolism of PAHs which are attributed to enhanced risk of lung cancer following exposure (Ezzeldin et al. 2017; Liu et al. 2019). CDC5L protein is a cell cycle regulator of the G2/M transition and was reported to participate in DNA damage repair and in the kinetochore-microtubule attachment (Mu et al. 2014). In addition, lung cancer risk was associated with PPP2R1A (Zhang et al. 2017) and HSP90AA1 (Wang et al. 2020).