Substrates of Human CYP2D6
Shufeng Zhou in Cytochrome P450 2D6, 2018
Dolasetron is a 5-HT3 receptor antagonist, which is used for the treatment of chemotherapy-induced emesis (Balfour and Goa 1997). It is rapidly reduced by carbonyl reductase to form its major pharmacologically active metabolite, reduced dolasetron (Shah et al. 1995). Reduced dolasetron appears in plasma within 10 min after intravenous or oral administration (Dempsey et al. 1996). Reduced dolasetron underwent oxidation of the indole aromatic ring at positions 5, 6, and 7 and also N-oxidation. Reduced dolasetron accounts for 17%–54% of the dose in urine, and hydroxylated metabolites of reduced dolasetron represent up to 9% of the dose in urine (Figure 3.37) (Reith et al. 1995). Most of the remaining urinary radioactivity consists of conjugated metabolites of reduced dolasetron and hydroxylated reduced dolasetron. Hydroxylation of reduced dolasetron is mediated by CYP2D6, and its N-oxidation is catalyzed by CYP3A4 (Sanwald et al. 1996a).
Ene-Reductases in Pharmaceutical Chemistry
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
As an alternative to the above-enumerated enzyme systems, carbonyl reductases have been employed to recycle the co-factor NAD(P)H by converting isopropanol into the volatile acetone (Mangan et al., 2012; Tauber et al., 2011). When using this approach, however, it is important to keep in mind that especially α,β -unsaturated aldehydes and, to a lesser extent, ketones may be reduced to the alcohol moiety by the carbonyl reductase leading to the formation of undesired side-products in form of the saturated and unsaturated alcohols.
Role of Genetic Variability in Breast Cancer Treatment Outcomes
Brian Leyland-Jones in Pharmacogenetics of Breast Cancer, 2020
Carbonyl reductase (CBR) is a monomeric, NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of carbonyl compounds, including doxorubicin and daunorubicin. In humans, two CBRs have been identified, CBR1 and CBR3. An SNP has been identified in CBR3 (CBR3 V244M), where the M244 isoform results in higher Vmax and is 100% more efficient in catalyzing the reduction of substrate (39). To our knowledge, CBRs have not been investigated in relation to breast cancer outcomes following treatment with anthracyclines.
Nucleoside diphosphate kinase 2 confers acquired 5-fluorouracil resistance in colorectal cancer cells
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Shaojia Wen, Xun Wang, Yamin Wang, Jianfeng Shen, Junyi Pu, Hui Liang, Chao Chen, Linna Liu, Penggao Dai
Among the regulated genes, the methylation of CBR1, UGT2A1 and RFC3 were all downregulated (β difference >0.3), indicating that these genes might involve in 5-FU chemoresistance to in CRC. Carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, catalyses the reduction of the ketone, aldehyde and C=C bond of ONE into 4-hydroxy-2-nonenal (HNE), 4-oxo-2-nonenol and 4-oxononanal, respectively [32]. This gene has been reported to mediate DOX reduction and suggested to develop the chemoresistance in cancer cells [33]. UGT2A1 belongs to UDP-glycosyltransferase family, which catalyse biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase water solubility and enhance excretion. They are of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds, UGT2A1 exhibited highest expression in the lung, colon and liver and other tissues [34], hence, it may play an important role in drug resistance. RFC3 mainly functioned in DNA replication, nucleotide excision repair and mismatch repair. It may affect the efficacy of drugs similar to paclitaxel’s and it also reported to over-expressed in many kinds of cancers. When RFC3 gene was silenced, ovarian tumour cells proliferation were greatly suppressed [35].
Valbenazine as the first and only approved treatment for adults with tardive dyskinesia
Published in Expert Review of Clinical Pharmacology, 2018
Harini Sarva, Claire Henchcliffe
TBZ’s metabolism is complex, as it is a racemate consisting of two ketone enantiomers, (+)- and (-)-tetrabenazine. Carbonyl reductase reduces the ketone moiety of both TBZ enantiomers to form active secondary alcohol metabolites, four in total due to the formation of an additional chiral center, which are collectively referred to as dihydrotetrabenazine (HTBZ) and individually referred to as (+)-α-HTBZ, (-)-α-HTBZ, (+)-β-HTBZ, and (-)-β-HTBZ [36,37]. Both (+)-α-HTBZ and (+)-β-HTBZ potently inhibit VMAT2 activity. However, both (-)-α-HTBZ and (-)-β-HTBZ are not potent VMAT2 inhibitors and bind to D2 receptors and other CNS relevant targets which may contribute to unwanted side effects of sedation and parkinsonism with chronic use [37].All four isomers are deactivated to O-demethylated and other metabolites by either CYP2D6 or CYP3A4 [36,37]. The α-enantiomers can be deactivated by either enzyme but the β-enantiomer isoforms are only deactivated by CYP2D6 [36,37]. This enzyme system’s activity varies among individuals and as a result of other medication interactions. In addition, CYP2D6 has genetic polymorphisms, and dihydrotetrabenazine products have a short half-life. As a result, TBZ is commonly prescribed as three times per day dosing [36]. This short half-life, complex metabolism, and side effects therefore resulted in the need for an improved TD treatment.
Evaluation of the drug–drug interaction potential for trazpiroben (TAK-906), a D2/D3 receptor antagonist for gastroparesis, towards cytochrome P450s and transporters
Published in Xenobiotica, 2021
Mitsuhiro Nishihara, Diane Ramsden, Suresh K. Balani
The reductase involved in [14C]trazpiroben metabolism was estimated based on the effect of reductase inhibitors using HLC. Typical reductase inhibitors were selected according to information in the literature (Rosemond et al.2004, Ramsden et al.2018). Phenobarbital, flufenamic acid, zopolrestat, chenodeoxycholic acid, and dexamethasone were used as aldo-keto reductase (AKR), 4-methylpyrazole was as an alcohol dehydrogenase inhibitor, disulphiram was as an aldehyde dehydrogenase inhibitor, quercetin and menadione were as short-chain dehydrogenase/reductase (SDR) and carbonyl reductase (CR) inhibitors, and dicumarol was as a quinone reductase inhibitor, respectively. The remaining activity was calculated as the percentage to the total radioactivity of the M23 peak in the sample with each inhibitor when the corresponding percentage in each control sample was regarded as 100%. The inhibition was calculated using the following equation: samp is the percentage to the total radioactivity of the M23 peak in the sample with each inhibitor (%) and PRcont is the percentage to the total radioactivity of the M23 peak in each control sample (%).
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