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Genetics and cancer
Published in Mark R Baker, Modernising Cancer Services, 2018
Apart from the dominant cancer syndromes, as mentioned previously, there are genetic polymorphisms which appear to be important in the development of cancer. Some polymorphisms may affect an individual’s response to various environmental exposures. It has been suggested that women with a particular (arginine) polymorphism at codon 72 of the p53 gene may have a higher risk of developing human papilloma virus (HPV)-associated cervical cancer than women with other polymorphisms.2 It has also been suggested that slow acetylators who carry the N-acetyltransferase 2 slow acetylation polymorphism and who smoke are at higher risk of bladder cancer (3 5%) than are fast acetylators who smoke (13%).3 However, there are conflicting results from different studies. Researchers are investigating the role of polymorphisms in certain genes, such as those for cytochrome P450 (CYP1A1 and CYP2E1) and glutathione-S-transferase (GSTM1 and GSTT1) in several different cancer types, including cancer of the cervix uteri, lung, oral cavity, bladder, prostate and oesophagus.
General toxicology
Published in Timbrell John, Study Toxicology Through Questions, 2017
N-acetyltransferase 2 . Thus slow acetylators have less functional enzyme than fast acetylators. The result is that detoxication by acetylation of hydrazines, sulphonamides and amines is decreased in slow acetylators. Toxic effects such as hydralazine-induced lupus and isoniazid-induced peripheral neuropathy are more common in the slow phenotype.
Urothelial and Urethral Cancer
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Ibrahim Jubber, Karl H. Pang, James W.F. Catto
Inheritance of low-cancer risk gene polymorphisms.Polymorphisms may be of unknown function:Such as those found in Chr. 19q12 by genome wide screens.Genes important in urothelial carcinogens metabolism are shown in Figure 24.1.N-acetyltransferase 2 (NAT-2)Regulates the rate of detoxification of aromatic amines (e.g., nitrosamine, a known urothelial carcinogens) through acetylation.Carriers of the ‘slow’ variant (because of a DNA polymorphism on one amino acid) of this gene have an increased risk of BC. Relative risk (RR) 1.4-fold compared with the ‘fast’ variant.Risk in slow variants is greater in tobacco smokers.56% of Caucasians are slow acetylators compared to 11% Asians.Glutathione S-transferase (GST)Encoded by the GSTM1 gene.Detoxifies polyaromatic hydrocarbons (PAHs).Homozygous deletion of GSTM1 gene (Null GSTM1) − BC RR 1.9 fold.
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.
Safety implications of combined antiretroviral and anti-tuberculosis drugs
Published in Expert Opinion on Drug Safety, 2020
Maddalena Cerrone, Margherita Bracchi, Sean Wasserman, Anton Pozniak, Graeme Meintjes, Karen Cohen, Robert J Wilkinson
The risk of hepatotoxicity may be increased by other acquired and genetic factors. As an example, N-acetyltransferase 2 (NAT2) acetylator status associates with INH-related DILI; those individuals classified as slow acetylators are at higher risk of hepatotoxicity [146]. Among studies investigating potential risk factors for development of liver injury during TB treatment, female sex, older age, low weight and alcohol consumption are associated with increased risk [123,128,147]. Hepatitis B and/or C chronic infections increase risk of liver injury and are associated with increased mortality during treatment of both sensitive and DR-TB [137,148]. Hence, screening for viral hepatitis is important at the start of TB treatment or when patients present with abnormal liver function during treatment. In addition, other concomitant medications known to be potentially hepatotoxic and frequently prescribed to PLWH with low CD4 count as treatment or prophylaxis for opportunistic infections (e.g. fluconazole and cotrimoxazole) should be stopped when liver injury develops on anti-TB drugs.