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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
As in other sites, nervous tissue biotransformation of foreign compounds is predominantly mediated through specific drug-metabolizing enzymatic systems, involving both Phase I and Phase II reactions. However, certain chemicals with close resemblance to endogenous substrates are often modified by brain enzymes associated with metabolism of endogenous compounds. Such is the case of l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a chemical causing a Parkinsonian syndrome which is clinically undistinguishable from idiopathic Parkinson’s disease. MPTP is metabol-ically activated to l-methyl-4-phenylpyridinium ion (MPP+) by monoamino oxidase B (MAO-B). This reaction is likely to occur within glial cells. MPP+ is then released from glial cells and actively accumulated into dopaminergic neurons (the ultimate target of MPTP/MPP+ neurotoxicity) by the catecholamine uptake system.67
Molecular Aspects of the Activity and Inhibition of the FAD-Containing Monoamine Oxidases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
A wide variety of amine-containing drugs are also metabolized by MAO, contributing 1% of the enzymatic metabolism of marketed drugs (compared to 95% by the P450 family) (Rendic and Guengerich, 2015). The biotransformation of drugs and other xenobiotics by the amine oxidases in contrast to the P450 family has been reviewed (Benedetti et al., 2001). Metabolism by MAO can also transform a compound into a toxic product. A well-known example is the four electron oxidation of l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by MAO to 1-methyl-4-phenylpyridinium (MPP+). The toxic MPP+ is taken up into dopaminergic cells in the substantia nigra and is accumulated into mitochondria where it inhibits NADH oxidation by the respiratory chain, hence preventing ATP production and consequent dopaminergic cell death leading to Parkinson’s disease (Singer and Ramsay, 1990). To avoid such adverse side effects in development of new compounds, computational methods for the prediction of probable metabolic products has been developed based on databases of approved drugs with well-characterized metabolic profiles (Kar and Leszczynski, 2017).
Nanonutraceuticals in Central Nervous System Disorders
Published in Bhupinder Singh, Minna Hakkarainen, Kamalinder K. Singh, NanoNutraceuticals, 2019
Amita Sarwal, Nisha Rawat, Gurpreet Singh, V. R. Sinha, Sumit Sharma, Dinesh Kumar
EGCG is a principle antioxidant compound of polyphenolic flavonoid obtained from green tea. EGCG inhibits Aβ (amyloid beta) fibril formation and oligomerization and subsequently minimizes β-amyloid instigated toxicity in hippocampal neurons. EGCG also protects SH-SY5Y neuroblastoma (human derived cell lines used in scientific research) in humans from the toxicity caused by amyloid precursor protein (APP), 3-hydroxykynurenine or 6-hydroxydopamine (6-OHDA) (Schroeder et al., 2009). Researchers have also demonstrated the preventive action of dopamine neurons from 1-methyl-4-phenylpyridinium (MPP+) toxicity. It has also been discovered that co-administration of EGCG prevented MPTP (1methyl-4phenyl-1236-tetrahydropyridine)-associated loss of dopamine neurons from the substantia nigra pars compacta.
Experimental models of chemically induced Parkinson’s disease in zebrafish at the embryonic larval stage: a systematic review
Published in Journal of Toxicology and Environmental Health, Part B, 2023
Paola Briñez-Gallego, Dennis Guilherme da Costa Silva, Marcos Freitas Cordeiro, Ana Paula Horn, Mariana Appel Hort
MPTP is the standard toxin or inducer of neuronal death in animal models, including rodents, nonhuman primates, fish, and invertebrates. Once inside the brain, MPTP is metabolized to MPP+ by monoamine oxidase-B (MAO-B) in glial cells, converting it into a neurotoxic molecule that affects dopaminergic neurons. MPP+ is selectively captured in dopaminergic neurons via DAT due to its structural similarity to the neurotransmitter (Martí et al. 2017). DAT actively takes up MPP+ and stores it within DA vesicles, which induces K+ efflux and cell membrane hyperpolarization, inhibiting neuronal activation (Yee et al. 2014). The toxicity of MPTP/MPP+ is mainly due to the inhibition of mitochondrial complex I of the electron transport chain, which leads to loss of ATP, mitochondrial dysfunction, ROS production, and changes in the antioxidant defense system (Gonzalezpolo et al. 2004).