Introduction to Human Cytochrome P450 Superfamily
Shufeng Zhou in 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).
Chemical Causes of Cancer
Peter G. Shields in Cancer Risk Assessment, 2005
Humans and some animals exhibit variations in genes encoding biotransformation enzymes that influence toxicity and carcinogenicity (227–231). Most of these allelic variations are due to single nucleotide polymorphisms (SNPs) which affect the catalytic activity of the encoded protein. Among the Phase I reactions, CYPIAI SNP has been linked to lung cancer risk in cigarette smokers (232). In a population exposed to PAH environmentally and through cigarette smoking, PAH adducts in lung tissue were greater in individuals with a combined CYP1A1 polymorphism and GST M1 (null) phenotype (233). CYP1B1 polymorphisms, which are numerous (234), include an SNP which is a susceptibility factor for head and neck cancers in cigarette smokers (235). Among male Japanese cigarette smokers, the normal genotype of CYP2A6 gene was associated with greater risk for lung cancer than a polymorphism which results in a lack of CYP2A6 activity (236). A polymorphism in CYP2E1, which catalyzes the activation of many nitrosa-mines (237), has been associated with increased risk of rectal cancer (238).
How much pharmacological therapy can be incorporated in primary lymphedema management?
Byung-Boong Lee, Peter Gloviczki, Francine Blei, Jovan N. Markovic in 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
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.
Impact of CYP2A6 gene polymorphism on the pharmacokinetics of dexmedetomidine for premedication
Published in Expert Review of Clinical Pharmacology, 2018
Ling Wang, Shaoming Wang, Juan Qi, Rongguo Yu, Jie Zhuang, Boyang Zhuang, Yongming Lou, Junshan Ruan, Hong Ye, Fangfang Lin
Dexmedetomidine is a clinically widely used sedative. Compared with similar drugs, it has no significant inhibition on respiration and can prevent delirium. Dexmedetomidine has also been reported on off-label usage of premedication, whose single dose is greater than that of other indications, but there are no relevant pharmacokinetic reports. That poses difficulties for drug safety and dose optimization.Previous studies have shown that there are individual differences in the pharmacokinetic characteristics of dexmedetomidine. Cytochrome P450 2A6 (CYP2A6) primarily mediates dexmedetomidine metabolism, which may easily lead to differences in individual pharmacokinetics based on genetic polymorphisms of metabolic enzymes. It is more representative to study the pharmacokinetics of dexmedetomidine based on CYP2A6 polymorphisms for anesthesia induction in Chinese population who have the highest mutation frequency of CYP2A6*4.Our study showed that T1/2β was consistent with published literature, but T1/2α was longer, V and Cl were lower in Chinese surgical patients adopting dexmedetomidine for anesthesia induction. The CYP2A6*4 polymorphism had no significant effect on the pharmacokinetics of dexmedetomidine, indicating that there is no need to consider this mutation in the dosage regimen design of dexmedetomidine in clinical practice.
Methoxsalen as an in vitro phenotyping tool in comparison with 1-aminobenzotriazole
Published in Xenobiotica, 2019
Raghava Choudary Palacharla, Parusharamulu Molgara, Hanumanth Rao Panthangi, Rajesh Kumar Boggavarapu, Arun Kumar Manoharan, Ranjith Kumar Ponnamaneni, Devender Reddy Ajjala, Ramakrishna Nirogi
Methoxsalen (also known as 8-MOP, psoralen) is a naturally occurring constituent found in the seeds of Ammi majus plant belonging to the family, Umbelliferae. Methoxsalen belongs to a group of chemical constituents known as furocoumarins. Methoxsalen is used for treating psoriasis, idiopathic vitiligo and cutaneous T-cell lymphoma. Methoxsalen acts as a photosensitizer and the skin reactivity to ultraviolet radiation is markedly enhanced in the presence of methoxsalen. It is a potent inhibitor of CYP2A6 in vitro and is used as a positive control inhibitor in the coumarin hydroxylation activity assay. Methoxsalen is also a potent metabolism-dependent inhibitor of CYP2A6 (Draper et al., 1997). Besides being a potent CYP2A6 inhibitor methoxsalen is an inhibitor of other cytochrome P450 (P450) enzymes (Nirogi et al., 2015; Zhang et al., 2001). 1-aminobenzotriazole (ABT) is being used as a nonspecific inactivator of P450 enzymes in the in vitro reaction phenotyping studies at a concentration of 1 mM in pre-incubation mode to distinguish the P450 mediated metabolism from non-P450 mediated metabolism. It is known that ABT can’t inhibit certain P450 enzyme activities, such as diclofenac hydroxylation mediated by CYP2C9 (Linder et al., 2009). There is a need for more suitable nonspecific inactivator that can distinguish the P450 mediated metabolism from non-P450 mediated metabolism to be used in phenotyping studies with human liver microsomes (HLM).
Related Knowledge Centers
- Cotinine
- Coumarin
- Nicotine
- Rifampicin
- Xenobiotic
- Cytochrome P450
- Endoplasmic Reticulum
- Enzyme Induction & Inhibition
- Phenobarbital