China
Africa
Explore chapters and articles related to this topic
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Clozapine is the first atypical antipsychotic developed and is first introduced in Europe in 1971 but is voluntarily withdrawn by the manufacturer in 1975 after it is shown to cause agranulocytosis that leads to death in some clozapine-treated patients. In 1989, the FDA approved clozapine’s use for treatment-resistant schizophrenia on the basis of the studies demonstrating that clozapine is more effective than any other antipsychotic for treating schizophrenia. The main metabolic pathways of clozapine consist of N-demethylation and N-oxide formation (Byerly and DeVane 1996). CYP1A2, 3A4, 2C9, 2C19, and 2D6 N-demethylate clozapine, while N-oxide formation is catalyzed by CYP3A4, 1A2, and flavin-containing monooxygenase 3 (FMO3) (Figure 3.22) (Eiermann et al. 1997; Fang et al. 1998; Linnet and Olesen 1997; Olesen and Linnet 2001; Tugnait et al. 1999). The estimated contribution of CYP1A2, 2C19, 3A4, 2C9, and 2D6 amounts to 30%, 24%, 22%, 12%, and 6%, respectively, with regard to the N-demethylation of clozapine in human liver microsomes (Olesen and Linnet 2001). CYP2D6 might play a role in the formation of metabolites other than N-demethylclozapine and the N-oxide (Fischer et al. 1992b). In addition, clozapine is extensively glucuronidated in vitro and in vivo by UGT1A4 (Mori et al. 2005).
Gut Microbiome
Published in Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss, Nutrition and Cardiometabolic Health, 2017
Brian J. Bennett, Katie A. Meyer, Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss
Thus, this meta-organismal pathway may be an important new paradigm to consider for an improved understanding of atherosclerotic heart disease and perhaps other cardiometabolic disease processes (Tang and Hazen 2014). We give a brief overview of this pathway with a focus on the metabolism of dietary nutrients. One route for the initial catabolism of dietary choline and l-carnitine (a nutrient important for fat metabolism) is mediated by intestinal microbes and leads to the formation of trimethylamine (TMA). Foods rich in choline and l-carnitine, such as eggs, milk, and red meat, can thus lead to increased TMA production (Zeisel et al. 2003). TMA is efficiently absorbed from the gastrointestinal tract and oxidized in the liver by the flavin-containing monooxygenase (FMO) enzymes to form trimethylamine N-oxide (TMAO) (Bennett et al. 2013). Studies have shown that Fmo3 is indeed the primary FMO responsible for hepatic metabolism of TMA to TMAO through a series of experiments that modulated Fmo3 mRNA levels using adenoviral overexpression, transgenic overexpression, and in vivo antisense oligonucleotides and examined the effect on circulating levels of TMAO (Bennett et al. 2013).
In Vitro to In Vivo Extrapolation of Metabolic Rate Constants for Physiologically Based Pharmacokinetic Models
Published in John C. Lipscomb, Edward V. Ohanian, Toxicokinetics and Risk Assessment, 2016
The endoplasmic reticulum of liver and other tissues also contains a second mixed-function oxidase system, the flavin-containing monooxygenases. This multigene family of enzymes utilizes electrons from NADPH to reduce molecular oxygen and monooxygenate polarizable heteroatoms, such as N, S, and P (36). Substrates for the flavin-containing monooxygenases include secondary and tertiary amines, hydrazines, thiocarbamates, thioamides, sulfides, disulfides, thiols, and other soft nucleophiles. Many of these substrates are oxidized with stereoselectivity, and this property has been used to distinguish oxidation by flavin-containing monooxygenases from CYP (36). Kinetic studies have shown that release of water from the enzyme–FAD complex is a slow step relative to substrate oxidation, so most substrates are oxidized with the same Vmax (37). Functional and genetic polymorphisms have been identified in human flavin-containing monooxygenase form 3 (38).
Metabolism of the areca alkaloids – toxic and psychoactive constituents of the areca (betel) nut
Published in Drug Metabolism Reviews, 2022
The piperidine ring of arecoline contains a tertiary amine which is susceptible to N-oxidation (Figure 2). N-oxidation is an important toxicologic event (e.g. forming hepatic toxins) common among other tertiary-amine-containing drugs of abuse, such as cocaine (Ndikum-Moffor et al. 1998) and nicotine (Xue et al. 2014). The work of Giri et al. (2007) showed that arecoline is converted to ANO by human recombinant flavin-containing monooxygenase enzyme-1 (FMO1) and to a lesser extent by FMO3. However, cDNA expressed P450 enzymes (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP4A11) did not significantly facilitate N-oxide formation (Giri et al. 2007). The role of FMO and CYP in catalyzing N-oxidation of arecaidine, however, was not studied.
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
Flavin-containing monooxygenase (FMO) protein family consists of a group of enzymes that metabolize drugs and xenobiotics and participate in the pharmacokinetics of nicotine. There are five forms of FMO, ranging from FMO1 to FMO5. Both FMO1 and FMO3 have been seen to be potentially susceptible genes for nicotine metabolism process. FMO6P is a pseudogene which has a significant sequence homology with FMO3. FMO1 contributes to the level of nicotine in the brain and FMO3 metabolizes a small part of nicotine to N'-nicotine oxide (Rossner et al.2017). As shown in Table 1, a comparative study between European Americans and African Americans observed a polymorphism (rs6674596; A > T) in FMO1 gene, associated with nicotine addiction in European Americans individuals (p = .0004; OR = 0.67, MAF = 0.135), but which was not associated in African Americans (p = .9325; OR = 1.01, MAF = 0.463). In African American individuals, a variant was identified in FMO6P, rs6608453 (C > T) which was not replicated in European Americans (p = .001, MAF = 0.097). However, in FMO3 gene no significant variants were found in any of the populations studied (Zhang et al.2017).
Differential effects of C-reactive protein levels on voriconazole metabolism at three age groups in allogeneic hematopoietic cell transplant recipients
Published in Journal of Chemotherapy, 2021
Xingxian Luo, Taifeng Li, Lei Hu, Silu Liu, Haiyan Zhao, Jiaqi Zhang, Yufei Feng, Lin Huang
Voriconazole (VRCZ), a second-generation broad-spectrum antifungal drug, is considered as the first-line treatment of invasive aspergillosis. It is commonly recommended to treat patients with progressive, potentially life-threatening infections in immunodeficient patients. VRCZ undergoes extensive Cytochrome P450 (CYP 450) isoenzymes metabolism, predominantly by CYP2C19 with a lesser extent by CYP3A4 and CYP2C9.1–3 The main metabolite of VRCZ, N-oxide VRCZ (VNO), which is primarily catalyzed by CYP2C19, has been reported that its less antifungal activity compares with VRCZ.4,5In vitro studies suggest that flavin-containing monooxygenase (FMO) is also one of the key isoenzymes involved in VRCZ metabolism.6