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Smoking cessation
Published in Claudio F. Donner, Nicolino Ambrosino, Roger S. Goldstein, Pulmonary Rehabilitation, 2020
Francesco Pistelli, Stefania Brogi, Laura Carrozzi
Nicotine inhaled by smoking tobacco is carried in smoke particles into the lungs, where it rapidly diffuses into the pulmonary venous circulation and enters the arterial circulation; it then rapidly moves to the central nervous system and diffuses into brain tissue. In about 10–20 seconds after a single puff, one-third of the inhaled nicotine binds to central nicotinic cholinergic receptors (the most abundant receptor subtypes in the brains of humans are alpha4 beta2). Nicotine is rapidly and extensively metabolized to cotinine by the liver, primarily by the enzyme CYP2A6, and it has an elimination half-life in chronic smokers of about 2 hours (12). As a consequence, nicotine blood levels are stable only if subjects smoke frequently.
How much pharmacological therapy can be incorporated in primary lymphedema management?
Published in Byung-Boong Lee, Peter Gloviczki, Francine Blei, Jovan N. Markovic, Vascular Malformations, 2019
There is also concern about the use of coumarin clinically due to reported hepatotoxicity. However, this may potentially be overcome through pharmacogenomics studies to target its use to those with a functional CYP2A6. A reduction of CYP2A6 results in the shunting of coumarin into other metabolic pathways, which can result in the production of cytotoxic metabolites such as o-hydroxy-phenylacetaldehyde rather than the beneficial 7-hydroxycoumarin, leading to hepatotoxicity.7, 8
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
The CYP2A6 gene spans ~6 kb in size consisting of nine exons and has been mapped to chromosome 19q13.2 (Fernandez-Salguero et al. 1995; Miles et al. 1989). It is located within a 350-kb gene cluster together with the CYP2A7 and 2A13 genes, two CYP2A7P pseudogenes, and genes in the CYP2B and CYP2F subfamilies on chromosome 19q (Fernandez-Salguero et al. 1995; Hoffman et al. 1995). CYP2A6 is mainly expressed in the liver accounting for approximately 1%–10% of total CYPs and is an important enzyme since it can metabolize approximately 3% of clinical drugs and is subject to polymorphism with significant clinical impacts (Di et al. 2009; Mwenifumbo and Tyndale 2007; Raunio and Rahnasto-Rilla 2012; Satarug et al. 2006). Only trace amounts of 2A6 are found in extrahepatic tissues such as nasal mucosa and lung (Chiang et al. 2012; Koskela et al. 1999). CYP2A6 has also been found to be expressed in steroid-related tissues such as adrenal gland, testis, ovary, and breast (Nakajima et al. 2006b).
The alteration of drug metabolism enzymes and pharmacokinetic parameters in nonalcoholic fatty liver disease: current animal models and clinical practice
Published in Drug Metabolism Reviews, 2023
Yan Zhu, Li Chen, Yuqi He, Lin Qin, Daopeng Tan, Zhaojun Bai, Yu Song, Yu-He Wang
In human and mouse models, the mRNA expression, protein level, and activity of CYP2A6 were all up-regulated (Fisher et al. 2009; Li et al. 2013; Wang et al. 2017; Wang et al. 2019). C57BL/6 mice were fed with the HFD for eight weeks, which resulted in significant inhibition of CYP2B6 activity (Wu et al. 2023). It was found that both mRNA and protein expression of CYP2C9 were decreased (Li, Clarke, et al. 2017). In hypertension rats, the activity of CYP2B6, CYP2D6, and Cyp2c29/CYP2C19 was all decreased (Niu et al. 2022). Simultaneously, the same trend was observed in HFD mice. In T2DM, the protein level and activity of Cyp2c29/CYP2C19 were all down-regulated (Yao et al. 2019; Kvitne et al. 2022). In humans, CYP2B6 and CYP2C9 mRNA expression increased with NAFLD progression, while both the mRNA and protein expression of CYP2E1 tended to decrease with NAFLD progression (Fisher et al. 2009). In contrast, the mRNA and protein expression of Cyp2e1 were up-regulated in HFD rats and mice (Zou et al. 2006; Li et al. 2011; Wang et al. 2020; Liu et al. 2022). The mRNA expression, protein level, and activity of CYP2E1 were all up-regulated in obesity, dyslipidemia, and metabolic syndrome mice and T2DM rats (Wang et al. 2018, 2019, 2020; Xu et al. 2019; Maksymchuk et al. 2022). In hypercholesterolemia, the mRNA and protein expression of CYP2E1 was also up-regulated in HFD mice (Wang et al. 2020), while both the mRNA expression and activity of CYP2E1 decreased in rats (Xu et al. 2022).
Metabolic activation of deferiprone mediated by CYP2A6
Published in Xenobiotica, 2021
Xiaojiao Zheng, Xu Wang, Zifang Ding, Wei Li, Ying Peng, Jiang Zheng
Recombinant human P450 enzyme incubation study showed that CYP2A6 played the major role in the metabolic activation of DFP (Figure 6). However, we cannot exclude the contribution of other P450 enzyme to the bioactivation, particularly multiple P450 enzymes are involved in the metabolic activation of DFP. Although some drugs are reportedly metabolized by human CYP2A6 but not necessarily by rat CYP2A1/2 (Messina et al. 1997; Miksys et al. 2000), rat CYP2A1/2 are known to share about 60% homology in amino acid sequence with human CYP2A6 (Martignoni et al. 2006). Our microsomal inhibition study showed that the presence of methoxsalen inhibited the formation of M3 in both human and rat microsomal incubations (Figure 7). Despite this, more work is in need to ensure rat CYP2A1/2 and human CYP2A6 share the similarity in catalysis of the metabolic activation of DFP.
Molecular docking and oxidation kinetics of 3-phenyl coumarin derivatives by human CYP2A13
Published in Xenobiotica, 2021
Risto O. Juvonen, Elmeri M. Jokinen, Juhani Huuskonen, Olli Kärkkäinen, Hannu Raunio, Olli T. Pentikäinen
Coumarin is the prototype substrate of both CYP2A13 and CYP2A6, and coumarin 7-hydroxylation is a marker activity for these enzymes (Fukami et al. 2007; Raunio and Rahnasto-Rilla 2012). CYP2A6 was somewhat more efficient in coumarin 7-hydroxylation than CYP2A13, as the Vmax by CYP2A13 was about twofold lower than that of CYP2A6, and the CYP2A13 Km was twofold higher. The observed Vmax and Km for CYP2A13 mediated coumarin 7-hydroxylation are in line with those reported earlier (von Weymarn and Murphy 2003; He et al. 2004; Su and Ding 2004). Docking analyses showed that in CYP2A13 steric hindrance by Ala301 orients coumarin slightly away from haem iron. Gly301 in CYP2A6 lets coumarin adopt a pose that brings 7-hydroxylation site closer to haem iron.