THE METABOLIC ACTIVATION OF RONIDAZOLE [(1-METHYL-5-NITROIMIDAZOLE-2-YL)-METHYL CARBAMATE] TO REACTIVE METABOLITES BY MAMMALIAN, CECAL BACTERIAL AND T. FOETUS ENZYMES

1986 ◽  
pp. 33-36
Author(s):  
GERALD T. MIWA ◽  
REGINA WANG ◽  
RAUL ALVARO ◽  
JOHN S. WALSH ◽  
ANTHONY Y.H. LU
Keyword(s):  
Metabolic Activation ◽  
Reactive Metabolites

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 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.

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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