The Effects of Experimental Diabetes on the Cytochrome P450 System and Other Metabolic Pathways
John H. McNeill in Experimental Models of Diabetes, 2018
CYP2B — One of the first subfamilies to be purified from the liver of animals, CYP2B has been extensively studied and shown to display broad substrate specificity.13 Although it metabolizes a large number of known chemical carcinogens, it tends to convert these to inactive metabolites and it is generally unable to convert them to their reactive intermediates.8 An activating role has, however, been ascribed to it in certain instances as in the case of certain long-chain aliphatic nitrosamines and drugs like cocaine and cyclophosphamide, where it acts as the major catalyst for the bioactivation of this anticancer drug to the pharmacologically active form in humans. Like CYP2A, in humans it is a minor form representing less than 2% of the total liver cytochrome P450, the isoforms being CYP2B6 and CYP2B7.
Introduction to Human Cytochrome P450 Superfamily
Shufeng Zhou in Cytochrome P450 2D6, 2018
This gene is part of a large cluster of cytochrome P450 genes from the CYP2A, CYP2B, and CYP2F subfamilies on chromosome 19q. It maps to chromosome 19q13.2 and contains nine exons. CYP2F1 is primarily expressed in lung with little or no hepatic expression (Carr et al. 2003; Wei et al. 2012). The −152 to −182 5′ region of CYP2F1 is identified as a specific promoter element that binds to a protein (Carr et al. 2003). This protein localizes to the ER and is known to dehydrogenate 3-methylindole, an endogenous toxin derived from the fermentation of tryptophan. CYP2F1 catalyzes the 7-ethoxy-and-propoxycoumarin O-dealkylation and 7-pentoxyresorufin O-depentylation. CYP2F1 can activate the lung toxicants 4-ipomeanol (Czerwinski et al. 1991), 3-methylindole, naphthalene (Lanza et al. 1999), and styrene (Nakajima et al. 1994).
Respiratory Tract Cancer
Peter G. Shields in Cancer Risk Assessment, 2005
Cytochrome P450 (CYP) enzymes are expressed at significant levels in the lung so that reactive genotoxic metabolites from PAHs and N-nitrosamines can be formed directly in the lung epithelium. Reactive metabolites may also migrate to the lung from distal organs (i.e., the liver) through the bloodstream inducing DNA damage. Several forms of P450 have been identified as playing a role in lung carcinogenesis. CYP1A1 and CYP2E1 are of critical importance for the activation of PAH and nitrosa-mines (and other low molecular weight compounds), respectively (31). The gene product of CYP1A1 catalyzes the first step in the metabolism of PAH. Recent studies indicate that the pulmonary system expresses several CYP enzymes although at low levels (32). Results show that CYP3A4, CYP1B1, and CYP2C9 also catalyze the formation of mutagenic intermediates from PAH. In addition to CYP2E1, the nitrosamines are also metabo-lically activated by CYP1A2, CYP2A6, and CYP2D6. CYP1A2 is expressed in peripheral lung, CYP2A6 is expressed in both bronchial epithelium and peripheral tissue. There is no detectable CYP2D6 expression in bronchus and lungs.
CYP2A6 gene variants may explain smoking status in a Turkish cohort
Published in Psychiatry and Clinical Psychopharmacology, 2019
Sacide Pehlivan, Mehmet Atilla Uysal, Tulin Cagatay, Ayse Feyda Nursal, Cigdem Kekik Cinar, Feyza Erkan, Ulgen Sever, Zuleyha Bingol, Mustafa Pehlivan, Sadrettin Pence
CYP2A6 enzyme is a member of an enzyme superfamily known as the cytochrome P450 system (CYP450), whichis classified in the drug metabolizing enzymes group [1]. These enzymes are located in the endoplasmic reticulum of the cells of several tissues in the body, especially in the liver. CYP2A6 metabolizes up to 70% of nicotine into cotinine through C-oxidation [3]. Several other enzymes of CYP450 such as CYP2B6, CYP2A13, CYP2D6 and CYP2E1 also play a minor role in the nicotine metabolism. The CYP2A6 gene (MIM 122720) was mapped to chromosome 19 where it is found within a 350-bp gene cluster along with the CYP2A7 and CYP2A13 genes [4]. The gene contains 9 exons spanning approximately 6 kb and encodes a protein with 494 amino acids [5]. The most common variants of this gene are single nucleotide polymorphisms (SNPs), which make CYP2A6 highly polymorphic, allowing it to produce isoforms that differ in enzymatic activity; hence, the nicotine level in the body differs from person to person. Smokers with distinct CYP2A6 variants manifest different smoking behaviours from those who do not bear these variants. This suggests that smokers regulate their nicotine consumption to maintain a certain drug level in the body [6]. CYP2A6 variability has a heterogeneous distribution in populations worldwide, which can explain the various metabolic responses to nicotine that are closely related with ND [1]. Even though some SNPs have been linked with ND in various ethnic populations, they are uncommon in Turkish populations.
Understanding the implications of the biobehavioral basis of nicotine addiction and its impact on the efficacy of treatment
Published in Expert Review of Respiratory Medicine, 2018
Nikki Bozinoff, Bernard Le Foll
The vast majority of nicotine clearance (~90%) occurs via metabolic (i.e. nonrenal) clearance [21]. CYP2A6 is the enzyme responsible for ~90% of the metabolic inactivation of nicotine to cotinine [22], and this pathway accounts for 70–90% of the total clearance of nicotine [23]. As stated previously, cotinine’s metabolism to 3HC is entirely catalyzed by CYP2A6 [24]. The rate of conversion of nicotine to its metabolites can vary between individuals due primarily to genetic variation in CYP2A6 enzymatic function, as well as some environmental influences. The gene encoding CYP2A6 is polymorphic, with more than 35 variant alleles, resulting in substantial interindividual variation in nicotine metabolism. The ratio of 3HC to cotinine (3HC/COT; also known as the nicotine metabolite ratio (NMR)) is a phenotypic biomarker of CYP2A6 enzymatic activity and, like CYP2A6 genotype, is associated with variation in smoking behavior. The utility of NMR as a biomarker of CYP2A6 activity among smokers derives from the exclusive metabolism of COT to 3HC by CYP2A6, as well as the relatively long half-life of COT (~16 h) and the formation dependence of 3HC [21,24,25]. NMR captures both genetic and environmental sources of variability in CYP2A6 activity, and is often used together with CYP2A6 genotype to investigate contributions of nicotine metabolism variation to smoking behaviors.
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).
Related Knowledge Centers
- Cotinine
- Coumarin
- Nicotine
- Rifampicin
- Xenobiotic
- Cytochrome P450
- Endoplasmic Reticulum
- Enzyme Induction & Inhibition
- Phenobarbital