General toxicology
Timbrell John in Study Toxicology Through Questions, 2017
Figure: Answer 9. Conjugation with #*glucuronic acid or *sulphate. (a) Azoreductase; (b) esterase/amidase; (c) N-acetyltransferase; (d) cytochrome P450; (e) epoxide hydrolase; (f) glutathione-S-transferase; (g) r-glutamyltransferase; (h) glycinase; (i) acetyltransferase. A10. The data in the table show that in both rats and mice the proportion of the dose of estragole metabolised to 1-hydroxyestragole increases as the dose of estragole given is increased, i.e. the metabolism is dose dependent. Therefore at the high doses used the production of the metabolite is increased. In the human, the proportion metabolised is even less, being only of the dose. Therefore with an intake of , the amount of 1-hydroxyestragole to which the human is exposed will be . The amount produced by mice at the carcinogenic dose will be of . Therefore the dose ratio between the two species based on the metabolism is . In other words, the mouse produces 10,000 million times more proximate carcinogenic metabolite at the carcinogenic dose than humans do at the expected dose.
The Opioid Epidemic
Sahar Swidan, Matthew Bennett in Advanced Therapeutics in Pain Medicine, 2020
Morphine also impacts epigenetic mechanisms that result in hyperalgesia and tolerance by changes in long-term gene expression in the pain system. Histone acetylation and deacetylation help to control gene expression. Histone acetyltransferase (HAT) enzymes transfer an acetyl group onto histones. The result is a more relaxed chromatin structure (euchromatin) and greater gene transcription. This relaxed structure can be “undone” by histone deacetylase (HDAC) transforming to a more condensed form (heterochromatin). Increasing morphine dose enhances the expression of acetylated histone H3 lysine9 (aceH3K9) in the dorsal spinal cord, which regulates the expression of dynorphin and brain-derived neurotrophic factor (BDNF).21 HAT inhibitors prior to morphine exposure (such as curcumin) have reduced the development of opioid-induced hyperalgesia.1,22 Conversely, HDAC inhibitor injections after morphine exposure prolong the morphine hyperalgesia and tolerance.22 Preventing the acetylation of histones or blocking BDNF or dynorphin may reduce hyperalgesia.
I
Caroline Ashley, Aileen Dunleavy, John Cunningham in The Renal Drug Handbook, 2018
The primary metabolic route is the acetylation of isoniazid to acetyl-isoniazid by N-acetyltransferase found in the liver and small intestine. Acetyl-isoniazid is then hydrolysed to isonicotinic acid and monoacetylhydrazine; isonicotinic acid is conjugated with glycine to isonicotinyl glycine (isonicotinuric acid) and monoacetylhydrazine is further acetylated to diacetylhydrazine. Some unmetabolised isoniazid is conjugated to hydrazones. The metabolites of isoniazid have no tuberculostatic activity and, apart from possibly monoacetylhydrazine, they are also less toxic. The rate of acetylation of isoniazid and monoacetylhydrazine is genetically determined and there is a bimodal distribution of persons who acetylate them either slowly or rapidly. In patients with normal renal function, over 75% of a dose appears in the urine in 24 hours, mainly as metabolites. Small amounts of drug are also excreted in the faeces.
Predicting the likelihood of bronchopulmonary dysplasia in premature neonates
Published in Expert Review of Respiratory Medicine, 2019
Patrick A Philpot, Vineet Bhandari
Chromatin packaging has long been known to have major effects on gene expression, especially through histone modification. Histone acetylation occurs via several histone acetyltransferase (HAT) proteins and their associated complexes. Recently, the role of histone deacetylases (Hdacs) has been linked to lung endoderm progenitor specification – in particular the class I Hdacs, Hdac1 and Hdac2. Furthermore, Wang et al. showed that Hdac3 and its associated epigenetic pathway is critical for the appropriate remodeling and expansion of distal lung saccules into primitive alveoli, which was supported by a reduction in alveolar type 1 cell spreading and disruption of sacculation with a loss of Hdac3 [90]. As sacculation precedes alveolarization in normal lung development, disruption in Hdac activity could further affect the risk of developing BPD.
Gene expression profiling of rat livers after continuous whole-body exposure to low-dose rate of gamma rays
Published in International Journal of Radiation Biology, 2018
Acetyl-CoA is at the center of lipid metabolism. Cytosolic acetyl-CoA synthesis, which is essential for de novo lipogenesis, was reduced in response to the low-dose-rate radiation. The cytosolic pool of acetyl-CoA is mainly supplied by two different ATP-dependent reactions: cleavage of citrate, which is generated from TCA cycle, into oxaloacetate and acetyl-CoA by ATP citrate lyase (ACLY) or the ligation of acetate and CoA by acetyl-CoA synthetase (ACSS) (Schug et al. 2015). Both ACLY and ACSS2, the cytosolic ACSS, were transcriptionally down-regulated in this study. Another pathway in producing cytosolic acetyl-CoA was through converting acetoacetate to acetoacetyl-CoA by acetoacetyl-CoA synthetase (AACS) and subsequently to acetyl-CoA by acetyl-CoA acetyltransferase 2 (ACAT2). This acetyl-CoA synthesis was also decreased as both Aacs and Acat2 genes were down-regulated.
Protein lysine acetylation and its role in different human pathologies: a proteomic approach
Published in Expert Review of Proteomics, 2021
Orlando Morales-Tarré, Ramiro Alonso-Bastida, Bolivar Arcos-Encarnación, Leonor Pérez-Martínez, Sergio Encarnación-Guevara
In this PTM, lysine acetyltransferase enzymes (KATs) acetylate a lysine residue; in contrast, lysine deacetylases (HDACs)remove the acetyl group. Additionally, in the mitochondria, where the presence of acetyltransferases has not yet been reported, the acetylation process has also been described. Consequently, there is substantial evidence that lysine acetylation might occur non-enzymatically; for this to happen, a concentration between 0.1 and 1.5 mM of acetyl-coenzyme A (AcCoA) and a pH between 7.9 and 8.7 is necessary [7]. The enzymatic acetylation process arises from transferring an acetyl group from AcCoA to the epsilon amino group in the lysine residue by KATs. On the other hand, the deacetylation procedure is carried out by HDACs by removing the acetyl group from the lysine residue, using Zn2+ or NAD+ (the latter in is additionally required the case of the sirtuins subfamily) to fulfill its function.
Related Knowledge Centers
- Acetylation
- Acyltransferase
- Chloramphenicol Acetyltransferase
- Choline Acetyltransferase
- Enzyme
- Histone Acetyltransferase
- Transferase
- Creb-Binding Protein
- Aralkylamine N-Acetyltransferase
- Nata Acetyltransferase