China
Africa
Explore chapters and articles related to this topic
Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
N-acetyltransferase type 2 (NAT2). NAT2 activity displays genetic polymorphism mediated by as an autosomal recessive trait [31]. Its distribution is extremely variable from one ethnic group to another. In Caucasian populations, 50 to 70% of individuals are slow acetylators, whereas the percentage is only 5% in Eskimo populations, and more than 90% in Egyptians [32].
Current Research on Alzheimer’s Disease In a Historical Perspective
Published in Zaven S. Khachaturian, Teresa S. Radebaugh, Alzheimer’s Disease, 2019
This awakening interest in Alzheimer’s disease in 1976 was further fueled by reports of the selective vulnerability of cholinergic neurons in the brain of Alzheimer’s disease patients independently emanating from three different laboratories in Great Britain.24,25 A putative role of acetylcholine in memory was provided by the knowledge that a cholinergic antagonist, scopolamine, had been used for decades as an amnesic drug by anesthesiologists, particularly in producing “twilight sleep” during childbirth so that the pain of childbirth would be forgotten. In 1974 Drachman and Leavitt26 had shown that scopolamine produced memory deficits in young volunteers not dissimilar from that observed in Alzheimer’s disease. Thus, measurement of the level of the acetylcholine biosynthetic enzyme choline acetyltransferase in Alzheimer’s disease brain became of interest. The marked reduction of choline acetyltransferase in cerebral cortex of Alzheimer patients reported by these groups was the first specific biochemical change reported for this disease. The reduction of choline acetyltransferase contrasted with the rather stable level of cholinergic receptors in the cerebral cortex of these same brains.
I
Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
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.
Relevance of gene polymorphisms of NAT2 and NR1I2 to anti-tuberculosis drug-induced hepatotoxicity
Published in Xenobiotica, 2022
Ning Wang, Shaochen Guo, Haiting Liu, Yangming Ding, Rong Yao, Zhongquan Liu, Hui Zhu, Xi Chen, Xinting Yang, Xiaoyou Chen, Yu Lu
Isoniazid, which is mainly metabolised and eliminated in the liver, is the most common drug associated with ATDH (Hussain et al. 2021). N-Acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) are the key enzymes in the metabolic pathway of isoniazid. The isoniazid metabolites, hydrazine and acetylhydrazine are likely to be oxidised partially by CYP2E1 into potentially hepatotoxic intermediates that can be dehydrated into compounds that bind covalently with macromolecules in hepatocytes, which eventually leads to hepatotoxicity (Preziosi 2007; Klein et al. 2016). A meta-analysis of 40 distinct patient cohorts demonstrated that the slow/intermediate genotype of NAT2 was a risk factor for ATDH (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.26–2.01) (Richardson et al. 2019). There are RsaI and PstI restriction sites in the transcription regulation region of CYP2E1, and a meta-analysis published in 2019 reported that together with the NAT2 slow acetylation genotype and glutathione S-transferases M1 (GSTM1) null genotype, CYP2E1 RsaI/PstI and c1/c1 polymorphisms are risk factors for ATDH among patients who have received anti-TB treatment (Yang et al. 2019).
N-Acetyltransferase 2, glutathione S-transferase gene polymorphisms and susceptibility to hepatocellular carcinoma in an Algerian population
Published in Xenobiotica, 2022
Lamia Chorfi, Azzedine Fercha, Faouzia Derouiche, Fatima Zohra Sebihi, Dallal Houhou, Keltoum Chorfi, Katia Bendjemana
The N-acetyltransferase 2 (NAT2) is a polymorphic gene, which is expressed predominantly in the liver and gut in a genotype-determined manner (Agúndez et al. 1996; Agúndez & García-Martín 2018). NAT2 is involved in the activation and inactivation of several carcinogenic compounds such as arylamines and N-hydroxylated heterocyclic amines present in tobacco smoke through N- or O-acetylation (Smith et al. 1994; Agúndez et al. 1996). Several allelic forms lead to variable acetylation status that can be slow or fast acetylation of potentially toxic substances (Hirvonen 1999). Previous studies reported the involvement of NAT2 in the development of hepatocellular carcinoma (Yu et al. 2000; Farker et al. 2003; Gelatti et al. 2005). However, the results are inconsistent.
N-acetyltransferase: the practical consequences of polymorphic activity in man
Published in Xenobiotica, 2020
There are many difficulties in interpreting the results from patient studies attempting to find associations between N-acetylation phenotype and the development or possession of a particular disease state. Most of the earlier studies have assessed acetylator status by orally dosing with a known substrate (e.g. isoniazid, sulfamethazine), collecting the subsequently voided urine or removed plasma samples and then calculating ratios following analysis for acetylated and non-acetylated compounds. The major organ being examined in such studies is the enzymatic activity of the liver, although any contributions from pre-systemic tissues, mainly the gastrointestinal tract, and the kidneys, are inseparable. Investigations have shown that the two isoforms of N-acetyltransferase show subtle but measurable differences in their substrate selectivity. The isoform NAT2 is more active towards sulfamethazine than NAT1, whereas NAT1 is more active with p-aminobenzoic acid and p-aminosalicylic acid (Dupret & Grant, 1992; Grant et al., 1991; Hein et al., 1993; Ohsako & Deguchi, 1990). It should be possible to be a rapid acetylator for NAT1 and a slow acetylator for NAT2 and vice versa. Whole body metabolism studies show an “average” of both reactions whereas genetic studies are “distant” from the actual enzymatic activities (Agundez & Garcia-Martin, 2018).