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Diseases of the Nervous System
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Methyl chloride and methyl bromide also exert some toxicity on the nervous system.12,321,419 Methyl chloride is an odorless gas at room temperature and applied in the production of synthetic rubber and plastic. Some cases of methyl chloride-induced neurotoxicity has been reported in workers exposed to this compound. The toxic symptoms include staggering gait, weakness, tremors, blurred vision, and impairment of short-term memory. These abnormalities persist for over 10 weeks after exposure. Long-term exposure to dichloromethane exerts irreversible effects on the brain.500
Reproductive System and Mammary Gland
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Justin D. Vidal, Charles E. Wood, Karyn Colman, Katharine M. Whitney, Dianne M. Creasy
Epithelial degeneration is uncommon as a drug-induced change. It has been described following dosing with methyl chloride (Chapin et al. 1984) where it was followed by an inflammatory response and the formation of sperm granulomas.
A Review of Epidemiologic Studies with Regard to Routes of Exposure to Toxicants
Published in Rhoda G. M. Wang, James B. Knaak, Howard I. Maibach, Health Risk Assessment, 2017
Since hemoglobin adducts have the same biological life span as hemoglobins in blood, they can provide a better index of recent exposure (including intermittent exposure) than measurements of metabolites in blood and urine. Methyl bromide has been shown to react with cysteine to form methylcysteine in hemoglobin. Studies of 14 methyl bromide workers suggested that methylcysteine (MeCys) in hemoglobin was a biological exposure index.39 Oral and inhalation exposures to three monohalomethanes (methyl bromide, methyl chloride, and methyl iodide) in rats showed highest binding to hemoglobin for methyl bromide, and higher binding via the inhalation vs. the oral route.40 These studies suggest that hemoglobin adducts should be explored further in human studies, including epidemiologic studies involving exposure to monohalomethanes. The genotoxic potential of certain monohalomethanes supports the need for such studies.
Using mechanistic information to support evidence integration and synthesis: a case study with inhaled formaldehyde and leukemia
Published in Critical Reviews in Toxicology, 2020
Robinan Gentry, Chad M. Thompson, Allison Franzen, Joshua Salley, Richard Albertini, Kun Lu, Tracy Greene
In addition, it should be noted that several compounds that are metabolized to formaldehyde have been evaluated and study results indicated no evidence of leukemia (Andersen et al. 2019). These include methyl chloride, methanol, caffeine, and aspartame (European Food Safety Authority 2014). Following oral administration of methanol (as a 15% solution in drinking water) to rats, 2- to 3-fold increases in formaldehyde DNA-reaction products were noted in bone marrow, kidney, and liver (Pontel et al. 2015). In another study, in which rats were dosed with 500 or 2000 mg methanol/kg/day for 5 days with mass-labeled 13CD4-methanol (Lu et al. 2012), increases in exogenous formaldehyde-DNA reaction products were noted in multiple tissues, including white blood cells. Thus, it is clear that following methanol administration, formaldehyde is produced in tissues throughout the body at sufficient concentrations to increase DNA-reaction products; however, evidence indicates that methanol exposure does not lead to the development of leukemia or other cancers (Cruzan 2009). Methyl chloride is also extensively metabolized to formaldehyde in rats (Kornbrust and Bus 1983). Following inhalation exposure of rats and mice to methyl chloride, significant increases in formaldehyde concentrations were reported in rat liver testes and brain, but not in nasal mucosa (Heck et al. 1982). Further, methyl chloride was carcinogenic only to the male mouse kidney and not in rats (Agency for Toxic Substances and Disease Registry 1998). Considering the available animal toxicology and human studies for formaldehyde-producing compounds provides a lack of any evidence for increased cancer in tissues in the hematopoietic system.
Synthesis and biological evaluation of 3–(4-aminophenyl)-coumarin derivatives as potential anti-Alzheimer’s disease agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Yu-Heng Hu, Jie Yang, Yun Zhang, Ke-Chun Liu, Teng Liu, Jie Sun, Xiao-Jing Wang
AChE belongs to serine hydrolase family of enzymes catalysing the hydrolysis of neurotransmitter ACh into choline and acetic acid, consequently causing cessation of cholinergic neurotransmission20. AChE is widely distributed in conducting tissues like nerves and muscles, central and peripheral tissues, motor, and sensory fibres in addition to cholinergic and non-cholinergic fibres21. It is also present in plasma and blood cells22,23. As shown in Table 2, only eight compounds (m, 4f, 4j, 4 l, 4o, 5a, 7 b, and 7d) presented moderate to excellent AChE inhibitory activity. Notably, 4 m (IC50 = 0.091 ± 0.011 μM) had relatively strong activity, which was weaker than donepezil (IC50 = 0.012 ± 0.001 μM). The target compounds with an aromatic heterocyclic ring (such as compounds 5a, 7b, and 7d have a furan ring, a naphthalene ring, and a thiophene ring, respectively) obtained by the amide condensation reaction and exhibited a good AChE inhibitory activity. Compounds 4d, 4m, and 4s contain methyl chloride at the same position. However, compound 4m with methoxy at R1 position has much better AChE inhibitory activity than compound 4s with methoxy at R1 position and hydroxyl groups at R2 position. At the same time, the activity of compound 4m is better than that of the compound 4d contained hydroxyl groups at R2 position. Compounds 4a, 4b, 4c, 4e, 4g, 4h, and 4i contained a hydroxyl group at R2 position and contained methyl, fluorine or chlorine, and these compounds have no inhibitory activity against AChE. The results indicated that compounds containing a methoxy group at R1 position and a methyl group, a fluorine atom or a chlorine atom (such as compounds 4g, 4k, 4m, 4o, 4p, and 4q), have a certain AChE inhibitory activity.