Amino acid and biogenic amine adductions derived from reactive metabolites

2021 ◽  
Vol 23 ◽  
Author(s):  
Zhengyu Zhang ◽  
Ying Peng ◽  
Jiang Zheng
Keyword(s):  
Normal Development ◽  
Lone Pair ◽  
Metabolic Activation ◽  
Reactive Metabolites ◽  
Dna And Protein Synthesis ◽  
Biochemical Mechanisms ◽  
Nitrogen Containing Compounds ◽  
Small Biomolecules ◽  
Synthesis Regulation ◽  
Exogenous Substances

: Reactive metabolites (RMs) are products generated from the metabolism of endogenous and exogenous substances. RMs are characterized as electrophilic species chemically reactive to nucleophiles. Those nucleophilic species may be nitrogen-containing bio-molecules, including macro-biomolecules, such as protein and DNA, and small biomolecules, i.e., amino acids (AAs) and biogenic amines (BAs). AAs and BAs are essential endogenous nitrogen-containing compounds required for normal development, metabolism, and physiological functions in organisms, through participating in the intracellular replication, transcription, translation, division and proliferation, DNA and protein synthesis, regulation of apoptosis, and intercellular communication activities. These biological amines containing an active lone pair of electrons on the electronegative nitrogen atom would be the proper N-nucleophiles to be attacked by the abovementioned RMs. This review covers an overview of adductions of AAs and BAs with varieties of RMs. These RMs are formed from metabolic activation of furans, naphthalene, benzene, and products of lipid peroxidation. This article is designed to provide readers with a better understanding of biochemical mechanisms of toxic action.

scholarly journals Brain manganese and the balance between essential roles and neurotoxicity

2020 ◽  
Vol 295 (19) ◽  
pp. 6312-6329 ◽  
Author(s):  
Rekha C. Balachandran ◽  
Somshuvra Mukhopadhyay ◽  
Danielle McBride ◽  
Jennifer Veevers ◽  
Fiona E. Harrison ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Normal Development ◽  
The Body ◽  
Neurological Dysfunction ◽  
Cellular Transport ◽  
Brain Health ◽  
Biochemical Mechanisms ◽  
Molecular And Biochemical Mechanisms ◽  
Neuronal Physiology ◽  
The Brain

Manganese (Mn) is an essential micronutrient required for the normal development of many organs, including the brain. Although its roles as a cofactor in several enzymes and in maintaining optimal physiology are well-known, the overall biological functions of Mn are rather poorly understood. Alterations in body Mn status are associated with altered neuronal physiology and cognition in humans, and either overexposure or (more rarely) insufficiency can cause neurological dysfunction. The resultant balancing act can be viewed as a hormetic U-shaped relationship for biological Mn status and optimal brain health, with changes in the brain leading to physiological effects throughout the body and vice versa. This review discusses Mn homeostasis, biomarkers, molecular mechanisms of cellular transport, and neuropathological changes associated with disruptions of Mn homeostasis, especially in its excess, and identifies gaps in our understanding of the molecular and biochemical mechanisms underlying Mn homeostasis and neurotoxicity.

scholarly journals Spontaneous Production of Glutathione-Conjugated Forms of 1,2-Dichloropropane: Comparative Study on Metabolic Activation Processes of Dihaloalkanes Associated with Occupational Cholangiocarcinoma

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Yu Toyoda ◽  
Tappei Takada ◽  
Hiroshi Suzuki
Keyword(s):  
Catalytic Activity ◽  
Positive Relationship ◽  
Metabolic Activation ◽  
Epidemiological Studies ◽  
The Other ◽  
Reactive Metabolites ◽  
Spontaneous Production ◽  
Occupational Cholangiocarcinoma ◽  
Spontaneous Reaction

Recently, epidemiological studies revealed a positive relationship between an outbreak of occupational cholangiocarcinoma and exposure to organic solvents containing 1,2-dichloropropane (1,2-DCP). In 1,2-DCP-administered animal models, we previously found biliary excretion of potentially oncogenic metabolites consisting of glutathione- (GSH-) conjugated forms of 1,2-DCP (GS-DCPs); however, the GS-DCP production pathway remains unknown. To enhance the understanding of 1,2-DCP-related risks to human health, we examined the reactivity of GSH with 1,2-DCP in vitro and compared it to that with dichloromethane (DCM), the other putative substance responsible for occupational cholangiocarcinoma. Our results showed that 1,2-DCP was spontaneously conjugated with GSH, whereas this spontaneous reaction was hardly detected between DCM and GSH. Further analysis revealed that glutathione S-transferase theta 1 (GSTT1) exhibited less effect on the 1,2-DCP reaction as compared with that observed for DCM. Although GSTT1-mediated bioactivation of dihaloalkanes could be a plausible explanation for the production of reactive metabolites related to carcinogenesis based on previous studies, this catalytic pathway might not mainly contribute to 1,2-DCP-related occupational cholangiocarcinoma. Considering the higher catalytic activity of GSTT1 on DCM as compared with that on 1,2-DCP, our findings suggested differences in the activation processes associated with 1,2-DCP and DCM metabolism.

Physiological importance of polyamines

Zygote ◽  
2017 ◽  
Vol 25 (3) ◽  
pp. 244-255 ◽  
Author(s):  
Yasser Y. Lenis ◽  
Mohammed A. Elmetwally ◽  
Juan G. Maldonado-Estrada ◽  
Fuller W. Bazer
Keyword(s):  
Cell Communication ◽  
Physiological Role ◽  
Arginine Decarboxylase ◽  
Animal Cells ◽  
Proline Oxidase ◽  
Polyamine Synthesis ◽  
Physiological Importance ◽  
Communication Activity ◽  
Dna And Protein Synthesis ◽  
Synthesis Regulation

SummaryPolyamines are polycationic molecules that contain two or more amino groups (–NH3+) and are present in all eukaryotic and prokaryotic cells. Polyamines are synthesized from arginine, ornithine, and proline, and from methionine as the methyl-group donor. In the traditional pathway for polyamine synthesis, arginase converts arginine into ornithine, which is decarboxylated by ornithine decarboxylase (ODC1) to generate putrescine. The latter is converted to spermidine and spermine. Recent studies have indicated the existence of ‘non-classical pathways’ for the generation of putrescine from arginine and proline in animal cells. Specifically, arginine decarboxylase (ADC) catalyzes the conversion of arginine into agmatine, which is hydrolyzed by agmatinase (AGMAT) to form putrescine. Additionally, proline is oxidized by proline oxidase to yield pyrroline-5-carboxylate, which undergoes transamination with glutamate to produce ornithine for decarboxylation by ODC1. Intracellular production of polyamines is controlled by antizymes binding to and inactivating ODC1. Polyamines exert effects that include stimulation of cell division and proliferation, gene expression for the survival of cells, DNA and protein synthesis, regulation of apoptosis, oxidative stress, angiogenesis, and cell–cell communication activity. Accordingly, polyamines are essential for early embryonic development and successful pregnancy outcome in mammals. In this paper the main concepts on the history, structure and molecular pathways of polyamines as well as their physiological role on angiogenesis, and reproductive physiology are reviewed.

THE ROLE OF METABOLIC ACTIVATION IN DRUG-INDUCED HEPATOTOXICITY

2005 ◽  
Vol 45 (1) ◽  
pp. 177-202 ◽  
Author(s):  
B. Kevin Park ◽  
Neil R. Kitteringham ◽  
James L. Maggs ◽  
Munir Pirmohamed ◽  
Dominic P. Williams
Keyword(s):  
Metabolic Activation ◽  
Chemical Carcinogenesis ◽  
Normal Liver ◽  
Covalent Modification ◽  
Reactive Metabolites ◽  
Drug Induced ◽  
Metabolite Formation ◽  
Toxic Species ◽  
Technological Developments ◽  
Hepatic Proteins

The importance of reactive metabolites in the pathogenesis of drug-induced toxicity has been a focus of research interest since pioneering investigations in the 1950s revealed the link between toxic metabolites and chemical carcinogenesis. There is now a great deal of evidence that shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, but how these toxic species initiate and propagate tissue damage is still poorly understood. This review summarizes the evidence for reactive metabolite formation from hepatotoxic drugs, such as acetaminophen, tamoxifen, diclofenac, and troglitazone, and the current hypotheses of how this leads to liver injury. Several hepatic proteins can be modified by reactive metabolites, but this in general equates poorly with the extent of toxicity. Much more important may be the identification of the critical proteins modified by these toxic species and how this alters their function. It is also important to note that the toxicity of reactive metabolites may be mediated by noncovalent binding mechanisms, which may also have profound effects on normal liver physiology. Technological developments in the wake of the genomic revolution now provide unprecedented power to characterize and quantify covalent modification of individual target proteins and their functional consequences; such information should dramatically improve our understanding of drug-induced hepatotoxic reactions.

Metabolic activation of 1,1-dichloroethylene by mouse lung and liver microsomes

1987 ◽  
Vol 65 (7) ◽  
pp. 1496-1499 ◽  
Author(s):  
P. G. Forkert ◽  
M. Hofley ◽  
W. J. Racz
Keyword(s):  
Carbon Monoxide ◽  
Covalent Binding ◽  
Liver Microsomes ◽  
Metabolic Activation ◽  
Reactive Metabolites ◽  
Mouse Lung ◽  
Nonspecific Binding ◽  
Liver Necrosis ◽  
Isolated Lung ◽  
Cytochrome P 450

1,1-Dichloroethylene (1,1-DCE) causes lung and liver necrosis in mice. Covalent binding of [14C] 1,1-DCE to isolated lung and liver microsomes from CD-1 mice required NADPH and was strongly inhibited by carbon monoxide. Lung and liver microsomes isolated from animals treated with phenobarbital demonstrated no changes in covalent binding of [14C]1,1-DCE compared with those from vehicle-treated animals. While 3-methylcholanthrene caused no alterations in binding to lung microsomes, the same pretreatment resulted in significantly increased levels of binding to liver microsomes. Piperonyl butoxide caused significant decreases in covalent binding to lung and liver microsomes; SKF 525-A significantly inhibited binding to liver microsomes but had no effect on lung microsomes. The incubation of liver microsomes with inhibitors required more NADPH than those performed with lung microsomes. The results demonstrate that reactive metabolites of 1,1-DCE can be formed by lung and liver microsomes, and suggest the involvement of cytochrome P-450 isozymes in the lung and liver injury induced by the halocarbon. However, metabolic activation by lung and liver microsomes may additionally involve non P-450 dependent mechanisms as evidenced by relatively high levels of nonspecific binding of 1,1-DCE.

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