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Aldehyde Oxidases as Enzymes in Phase I Drug Metabolism
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Cristiano Mota, Teresa Santos-Silva, Mineko Terao, Enrico Garattini, Maria João Romão, Silke Leimkühler
AOX enzymes are better known for oxidizing different types of aldehydes to their corresponding acids being also involved in the hydroxylation of N-heterocyclic ring systems possessing –CH=N– moieties (e.g., phthalazine) and purine or aromatic and non-aromatic charged heterocycles with a –CH=N+ group (e.g., N1-methylnicotinamide and N-methylphthalazinium). Thus, the term “aldehyde oxidase” might not always be appropriate, since these enzymes do not necessarily act on substrates containing an aldehyde functionality (Coelho et al., 2012; Garattini and Terao, 2011).
Body weight predicts Nicotinamide N-Methyltransferase activity in mouse fat
Published in Endocrine Research, 2018
Bianca Rudolphi, Benedikt Zapp, Nils A. Kraus, Franziska Ehebauer, Bettina J. Kraus, Daniel Kraus
Many studies, including those of the role of NNMT in energy metabolism, report NNMT mRNA and protein expression levels.1,13 There are however several published enzyme activity assays. In their pioneering work on NNMT enzymology, Weinshilboum and colleagues contrived a radioactive assay which involves organic extraction of the reaction product, 1-[14C]methylnicotinamide, with 1-heptanesulfonate using a mixture of isoamyl alcohol and toluene.3,14 This assay produces large amounts of radioactive organic waste which is hazardous and costly to dispose. An alternative is chromatography and mass spectrometry of the amount of 1-methylnicotinamide that is produced by the enzymatic reaction.15,16 While this assay is specific and may allow high-throughput sampling, it involves sophisticated instrumentation and technical expertise.
Recent developments in in vitro and in vivo models for improved translation of preclinical pharmacokinetics and pharmacodynamics data
Published in Drug Metabolism Reviews, 2021
Jaydeep Yadav, Mehdi El Hassani, Jasleen Sodhi, Volker M. Lauschke, Jessica H. Hartman, Laura E. Russell
Neyshaburinezhad et al. recently studied the changes in liver enzymatic activity of CYP2D1 and its related hepatic clearance in a type I and II diabetes rat model after treatment with insulin and metformin. The post-treatment effects of insulin and metformin administration on CYP2D1 activity and hepatic clearance were examined by measuring changes in the ratio of dextrorphan to dextromethorphan in a type I and II diabetic rat perfused liver model. For induction of type I diabetes, 65 mg/kg streptozotocin (STZ) was injected intraperitoneally overnight to fasted male Sprague-Dawley rats (Neyshaburinezhad et al. 2020). STZ damages the Langerhans islets β cells, resulting in hypoinsulinemia and hyperglycemia (Shah and Smith 2015). Type II diabetes was induced by intraperitoneal injection of 110 mg/kg nicotinamide followed by intraperitoneal injection of streptozotocin. Nicotinamide is methylated in vivo by nicotinamide N-methyltransferase into N1-methylnicotinamide which is associated with oxidative stress and insulin resistance at high concentrations (Országhová et al. 2012). Treatment was initiated one week after disease induction to maximize the potential effects of diabetes on increasing levels of proinflammatory cytokines, and therefore, CYP2D1 activity (Neyshaburinezhad et al. 2020). It was found that type I diabetes significantly decreased the activity of CYP2D1 (i.e. significant decrease in mean metabolic ratios of the untreated rats compared to the control group). Although mean metabolic ratios decreased in type II diabetic rats, the difference was not statistically significant. The study also demonstrated a decrease in hepatic clearance of dextromethorphan in type I and II diabetic rats.