Aldehyde oxidase at the crossroad of metabolism and preclinical screening

Site-Directed Mutagenesis at the Molybdenum Pterin Cofactor Site of the Human Aldehyde Oxidase: Interrogating the Kinetic Differences Between Human and Cynomolgus Monkey

“…In humans, only the AOX1 gene shows activity and the other two pseudogenes (AOX2 and AOX4) remain inactive despite being transcribed. The same trend is observed in chimpanzees, demonstrating that this functional inactivation of AOX4 and AOX2 occurred before the human speciation occurred (Garattini et al, 2009;Cheshmazar et al, 2019).…”

“…The complicated interspecies differences for AO may have arisen due to the presence of various isoforms in different species or the multiple active sites present in this enzyme (Hoshino et al, 2007;Garattini et al, 2009;Paragas et al, 2017a) The number of AOX active genes in traditional preclinical species varies from none in dogs hepatocytes to the extreme of four in rodents (Garattini et al, 2009). When more than one AO isozyme is present in a species, they typically exhibit tissue specificity (Cheshmazar et al, 2019). In humans, only the AOX1 gene shows activity and the other two pseudogenes (AOX2 and AOX4) remain inactive despite being transcribed.…”

Short and long-term associations between serum proteins linked to cardiovascular disease and particle exposure among constructions workers

“…The human aldehyde oxidase (HAOX1) is a molybdenum enzyme involved in metabolism of xenobiotics ( 37 ). HAOX1 is part of phase I liver metabolism and has been shown to affect clinical efficiency of novel drugs and contribute to drug failure ( 38 ). In vitro exposure of lung cells to particles (gasoline combustion particles) resulted in decreased gene expression of AOX1 gene ( 15 ).…”

Biotransformation: Impact and Application of Metabolism in Drug Discovery

“…One consequence of the current practice of selection of molecules during the discovery phase that have high metabolic stability in liver microsome systems is that alternative non-CYP pathways are now becoming more prevalent as clearance mechanisms, such as those mediated by aldehyde oxidase, and which can result in some unwelcome surprises in the clinic due to unexpectedly high clearance of the drug. , Aldehyde oxidase (AO) is not only present in the liver but is extensively expressed extrahepatically with wide differences in expression across animal species. To alleviate concerns about differences in AO enzyme expression between species used for preclinical assessment and humans, one recent study examining two AO-mediated metabolites of a methylquinoline-containing drug candidate used early in vitro and in vivo models to ensure adequate animal species coverage to predict relatively high exposure of one of the AO metabolites in human plasma …”