Basic psychopharmacology
Jonathan P Rogers, Cheryl CY Leung, Timothy RJ Nicholson in Pocket Prescriber Psychiatry, 2019
The cytochrome P450 (CYP) enzyme system is the most important in drug metabolism, the most significant being CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Some drugs have significant metabolism via other routes though. CYP2D6 is the most genetically variable cytochrome enzyme: 7% of Caucasians are poor metabolisers and up to 29% of Black people are very fast metabolisers (Davies & Nutt, Psychiatry 2007; 6(7): 268–72).Up to 25% of East Asians are CYP2C19 poor metabolisers (Davies & Nutt, Psychiatry 2007; 6(7): 268–72).See p. 341, refer ‘Enzyme Interactions’ heading in this chapter for specific cytochrome interactions.
Biomarkers of Toxicant Susceptibility
Anthony P. DeCaprio in Toxicologic Biomarkers, 2006
The P450 2E1 cytochrome (CYP2E1) metabolizes many indirect carcinogens such as nitrosoamines (N-nitrosodimethylamine and N-nitrosopyrrolidine), some components of tobacco smoke, and many chlorinated and nonchlorinated solvents, including benzene. CYP2E1 may be induced by ethanol, and thus alcohol intake may influence carcinogenesis by exposure to carcinogens activated by this enzyme. In man, it is mainly expressed in liver, with a high degree of variability. Gene CYP2E1 reveals one of the most complex cases of polymorphism nomenclature. CYP2E1*1 is the wild or normal type (10). Allele CYP2E1*2 was attributed to the first polymorphism discovered in 1987 by McBride et al. (12), and consists of a C>G mutation in intron 7, which creates a restriction site for enzyme Taq1. Two polymorphisms (CYP2E1*3 and CYP2E1*5) are recognized by the restriction enzyme Rsa1. Unlike *5, *3 results from loss of the restriction site for Rsa1, and is in complete linkage disequilibrium with another restriction site recognized by Pts1. Two other polymorphisms also have been discovered, CYP2E1 *4 and *6, the former due to a mutation involving loss of the restriction site for enzyme Dra1 and the latter recognized by restriction enzyme Msp1. All these polymorphisms are located in the noncoding region of CYP2E1 and appear to act on the transcriptional regulation of the enzyme, increasing its activity.
Occupational Cancer
Peter G. Shields in Cancer Risk Assessment, 2005
An example of markers of risk is the relationship of polymorphic variants of cytochrome P450 in the metabolic activation of precarcinogens. Many Phase I P450 enzymes bioactivate carcinogens, whereas Phase II enzymes participate in the deactivation process. Both the CYP1A1 and CYP2E1 variants of Phase I P450 enzymes are involved in the metabolism of many suspected and established carcinogens. Since genetic polymorphisms have been identified for both Phase I and Phase II enzymes, risk assessments could be enhanced if polymorphisms in both enzyme categories are considered as biomarkers for susceptibility to cancer (30). Genetic and molecular epidemiology research involving the use of biomarkers also raises ethical questions, related to the potential for such information to be used for discriminatory purposes (31–33).
Inhibitory effect of chlormethiazole on the toxicokinetics of diethylnitrosamine in normal and hepatofibrotic rats
Published in Drug and Chemical Toxicology, 2019
Gaoju Wang, Kang Xiao, Jie Gao, Shan Jiang, Shang Wang, Shijia Weng, Chen Xu, Tong Wang, Hai-Ling Qiao
Cytochrome P450 2E1 (CYP2E1), one of the xenobiotic-metabolizing P450s in the liver, is strongly associated with the metabolism of a wide range of endogenous and exogenous chemicals (Wang et al.2016). It is of interest because of its ability to convert many toxicologically important substrates including ethanol, carbon tetrachloride, acetaminophen, and N-nitrosodimethylamine to reactive intermediates that may elicit organ damage and tumorigenesis (Abdelmegeed et al.2017, Gao et al.2017). Furthermore, it has been shown that CYP2E1 is the most effective catalyst of ethanol oxidation among the human P450 enzymes, and may play an important role in chronic alcohol-induced liver injury (Seitz and Wang 2013). The induction of CYP2E1 expression by chronic alcohol intake enhances its ability to generate reactive oxygen species, enhances the activation of procarcinogens to carcinogens, and increases hepatic necrosis and cellular apoptosis in response to the increased release of the cytokine tumor necrosis factor-alpha (TNF-α), which may contribute to hepatocarcinogenesis (Dinis-Oliveira 2016, Na et al.2017).
Evaluation of enzymatic and non-enzymatic antioxidant status and biomarkers of oxidative stress in saliva of patients with oral squamous cell carcinoma and oral leukoplakia: a pilot study
Published in Acta Odontologica Scandinavica, 2019
Karolina Babiuch, Anna Bednarczyk, Katarzyna Gawlik, Dorota Pawlica-Gosiewska, Barbara Kęsek, Dagmara Darczuk, Patryk Stępień, Maria Chomyszyn-Gajewska, Tomasz Kaczmarzyk
We also found that levels of some salivary biomarkers may be related to the degree of alcohol consumption and cigarette smoking which are the two most important risk factors of oral cancer development. In alcoholics, free radicals are produced in excessive amounts [39]. Oxidation of ethanol by cytochrome P450 2E1 (CYP2E1) generates acetaldehyde (the most toxic ethanol metabolite) but also reactive oxygen species. The production of the latter leads to lipid peroxidation and formation of its by-products, such as 4-hydroxynonenal (4HNE), which binds to DNA to induce mutagenic adducts [40]. Results of the present study revealed that alcohol intake may influence non-enzymatic and enzymatic components of antioxidant defence system. Interestingly, non-drinkers had lower TAC as compared to moderate but not to heavy drinkers, which may suggest that alcohol intake increases total antioxidant capacity but only to some degree. By contrast, levels of SOD were found to be higher in both moderate and heavy drinkers than in non-drinkers. This might be related to higher adaptability of enzymatic part of antioxidant defence (particularly the first line of defence against reactive oxygen species in the cell provided by SOD) in response to increased production of ROS, as compared to its non-enzymatic counterpart.
Selenium, a dietary-antioxidant with cardioprotective effects, prevents the impairments in heart rate and systolic blood pressure in adolescent rats exposed to binge drinking treatment
Published in The American Journal of Drug and Alcohol Abuse, 2021
M Luisa Ojeda, Paula Sobrino, Rui Manuel Rua, María del Carmen Gallego-Lopez, Fátima Nogales, Olimpia Carreras
It is known that in adults acute ethanol-induced heart alterations are related mainly to its oxidative metabolism; i.e., acetaldehyde and aldehyde dehydrogenases. More than one mechanism is often activated, which leads to multiple changes in cellular proteins and associated cell functions. For instance, Piano and Phillips (7) revealed important roles for oxidative stress (OS) and the hormone angiotensin II. In this context, it is important to remember that acute ethanol administration during the above indicated oxidative metabolism induces cytochrome P450 2E1 (CYP2E1) activity. Noteworthy is the fact that CYP2E1 is a powerful generator of reactive oxygen species (ROS) (8). Excessive oxidation can, moreover, activate the sympathetic nervous system (SNS) as well as the renin-angiotensin-aldosterone system (RAAS) (9). BD may also adversely affect lipid profiles and hemostatic/coagulation mechanisms, leading to severe peripheral endothelial dysfunction which affects coronary arteries and heart function. It is also known that a BD pattern directly affects heart function, since it provokes OS and apoptosis as well as increasing the vulnerability for arrhythmias by altering myocardial electrophysiological properties (10,11).