Long-term 1,2-dimethylhydrazine triggers pathological remodeling of colon mucosa through repression of sestrin2, nuclear factor (erythroid-derived 2)-like 2, and sirtuin4 stimulating mitochondrial stress and metabolic reprogramming

1,2-Dimethylhydrazine (DMH) is a plant toxicant that enters the food web through the diet. It is biotransformed into azoxymethane, a colon carcinogen, during the first hepatic passage. In mice, this study assessed the role of glutamate dehydrogenase (GDH), a key glutaminolysis enzyme in DMH-induced...

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Published in:Naunyn-Schmiedeberg's archives of pharmacology 2023-06, Vol.396 (6), p.1291-1307
Main Authors: Allal, Bader-Edine, Bounaama, Abdelkader, Silva, Dany, Quintas, Clara, Dahlouk, Salim Ismail, Gonçalves, Jorge, Djerdjouri, Bahia
Format: Article
Language:English
Subjects:
1,2-Dimethylhydrazine
1,2-Dimethylhydrazine - adverse effects
1,2-Dimethylhydrazine - metabolism
Allosteric properties
Animals
Azoxymethane
Biomedical and Life Sciences
Biomedicine
Carcinogens
Cell migration
Cell viability
Colon - metabolism
Colon cancer
Colonic Neoplasms - chemically induced
Colonic Neoplasms - metabolism
Colorectal carcinoma
Dehydrogenases
Epigallocatechin gallate
Food webs
Glutamate dehydrogenase
Glycolysis
Homeostasis
Humans
L-Lactate dehydrogenase
Metabolism
Mice
Mitochondria
Mucosa
Mucous Membrane
Neurosciences
Pharmacology/Toxicology
Rats
Rats, Wistar
Reactive Oxygen Species - metabolism
Regulatory sequences
Toxicants
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Summary:1,2-Dimethylhydrazine (DMH) is a plant toxicant that enters the food web through the diet. It is biotransformed into azoxymethane, a colon carcinogen, during the first hepatic passage. In mice, this study assessed the role of glutamate dehydrogenase (GDH), a key glutaminolysis enzyme in DMH-induced colorectal cancer (CRC). Colon samples were taken from mice given 6 or 15 weekly doses of 20 mg/kg DMH and serially sacrificed. Repeated DMH doses induced early aberrant crypt foci that evolved into irreversible adenocarcinomas over 24 weeks, along with an increase in GDH and lactate dehydrogenase activities (+ 122%, + 238%, P  
ISSN:0028-1298
1432-1912
DOI:10.1007/s00210-023-02403-x