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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.
Pharmacological Management of Parkinson’s Disease
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Newman Osafo, Samuel Obeng, David D. Obiri, Oduro K. Yeboah, Leslie B. Essel
In addition to N-demethylation, orphenadrine is also metabolized via deamination and conjugation with 60% excretion via the renal system within 72 h. Only 8% of the drug is excreted unchaged (Guo et al., 1997). The drug interacts with CYP2B6 and CYP2D6, and cause up to 45–57% and 80–90% reduction in microsomal enzymes, respectively (Ellison, 1972). CYP1A2, CYP2A6, CYP3A4, and CYP2C19 marker activities are however decreased to a lesser extent. Only about a percentage of biperiden is excreted unmetabolized in urine with a chunk of the drug metabolized (Grimaldi et al., 1986).
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
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
The respiratory system consists of tissues that are ports of entry for inhaled chemicals. CYPs and other xenobiotic-metabolising enzymes are expressed at every level of the respiratory tract, starting from nasal epithelial, and ending in lung alveoli (Hukkanen et al. 2002; Oesch et al. 2019). Of the two functional enzymes in the human CYP2A subfamily, CYP2A6 is abundant in liver, whereas CYP2A13 is expressed in extrahepatic tissues. CYP2A13 is expressed especially in nasal mucosa and lung (Raunio and Rahnasto-Rilla 2012). CYP2A13 and CYP2A6 share 95.4% amino acid identity Fernandez-Salguero et al. 1995). In the respiratory system, several compounds are bioactivated from pro-toxic forms to ultimate toxic metabolites (Pelkonen and Raunio 1997; Anttila et al. 2011; Oesch et al. 2019). CYP2A13 mediated bioactivation plays a role in lung tumorigenesis. CYP2A13 activates many procarcinogens in tobacco, including the tobacco-specific N-nitrosamines 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N9-nitrosonornicotine (NNN) (Su and Ding 2004; Jalas et al. 2005; Zhang et al. 2007), naphthalene, phenanthrene, biphenyl (Shimada et al. 2016; Li et al. 2017), and 5-hydroxymethylfurfural (Ji et al. 2018). Other notable examples of compounds metabolised by CYP2A13 are aflatoxins (He et al. 2006; Zhang et al. 2013), nicotine (Hukkanen et al. 2005; Murphy et al. 2005) and coumarin (Fukami et al. 2007).
Genetic susceptibility to nicotine and/or alcohol addiction: a systematic review
Published in Toxin Reviews, 2021
Isabel Legaz, M. D. Pérez-Cárceles, Irene de la Calle, Fuensanta Arjona, Miriam Roca, Pablo Cejudo, Aurelio Luna, Eduardo Osuna
The effect of CYP2A6*4 genetic polymorphisms on smoking behavior and nicotine dependence was analyzed in Japanese men (Ito et al.2015). The results showed that CYP2A6*4 genetic polymorphisms may not affect smoking behavior strongly but may possibly have an effect on nicotine dependence. Another study analyzed variations in CYP2A6 and CYP2B6 genes and their relation with tobacco dependence during adolescence and in young adult smokers (Chenoweth et al.2016), finding that only people who carry CYP2A6*2 or CYP2A6*4 alleles had at a higher risk of developing tobacco dependence, but nevertheless the role of genetic variations in CYP2B6 in smoking acquisition and dependence remains to be clarified. The CYP2A6*4 allele, in which CYP2A6 is a homozygous whole-deletion variant, completely lacks enzyme activity.
Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease
Published in Xenobiotica, 2020
Ian R. Phillips, Elizabeth A. Shephard
Another example of a drug substrate of FMO3 that is subject to multi-pathway metabolism is the stimulant nicotine. The major pathway of nicotine metabolism is mediated by CYP2A6 (Cashman et al., 1992; Nakajima et al., 1996), with only 4–7% of nicotine equivalents being excreted as its N-oxide (Benowitz et al., 1994), a product formed by FMO3 (Cashman et al., 1992). However, in individuals homozygous for a deletion of CYP2A6 as much as 30% of absorbed nicotine is excreted as the N-oxide (Yamanaka et al., 2004). Genetic variants of FMO3 that influence nicotine metabolism (Teitelbaum et al., 2018), would, therefore, be expected to be of greater importance in individuals with compromised CYP2A6 activity, and there is evidence that this is the case (Perez-Paramo et al., 2019).