Abstract
Aldehyde oxidase (AOX) is a soluble, cytosolic enzyme that metabolizes various N-heterocyclic compounds and organic aldehydes. It has wide tissue distribution with highest levels found in liver, kidney, and lung. Human clearance projections of AOX substrates by in vitro assessments in isolated liver fractions (cytosol, S9) and even hepatocytes have been largely underpredictive of clinical outcomes. Various hypotheses have been suggested as to why this is the case. One explanation is that extrahepatic AOX expression contributes measurably to AOX clearance and is at least partially responsible for the often observed underpredictions. Although AOX expression has been confirmed in several extrahepatic tissues, activities therein and potential contribution to overall human clearance have not been thoroughly studied. In this work, the AOX enzyme activity using the S9 fractions of select extrahepatic human tissues (kidney, lung, vasculature, and intestine) were measured using carbazeran as a probe substrate. Measured activities were scaled to a whole-body clearance using best-available parameters and compared with liver S9 fractions. Here, the combined scaled AOX clearance obtained from the kidney, lung, vasculature, and intestine is very low and amounted to <1% of liver. This work suggests that AOX metabolism from extrahepatic sources plays little role in the underprediction of activity in human. One of the notable outcomes of this work has been the first direct demonstration of AOX activity in human vasculature. SIGNIFICANCE STATEMENT: This work demonstrates aldehyde oxidase (AOX) activity is measurable in a variety of extrahepatic human tissues, including vasculature, yet activities and potential contributions to human clearance are relatively low and insignificant when compared with the liver. Additionally, the modeling of the tissue-specific in vitro kinetic data suggests that AOX may be influenced by the tissue it resides in and thus show different affinity, activity, and modified activity over time.
Highlights
Aldehyde oxidase is a molybdenum cofactor-containing cytosolic enzyme recognized for its potential to oxidize various nitrogen-containing heterocyclic compounds and organic aldehydes (Beedham, 2001; Kitamura et al, 2006; Garattini et al, 2008; Pryde et al, 2010; Terao et al, 2016; Rashidi and Soltani, 2017)
Taken together, observed data in human S9 fractions without cofactors suggest that carbazeran is metabolized to a single product, 4-oxo-carbazeran, and this is mediated by the aldehyde oxidase (AOX) pathway
The human liver is the richest source of AOX, the current study has demonstrated that AOX activity is clearly present and measurable in a variety of extrahepatic human tissues
Summary
Aldehyde oxidase is a molybdenum cofactor-containing cytosolic enzyme recognized for its potential to oxidize various nitrogen-containing heterocyclic compounds and organic aldehydes (Beedham, 2001; Kitamura et al, 2006; Garattini et al, 2008; Pryde et al, 2010; Terao et al, 2016; Rashidi and Soltani, 2017). Apart from oxidation reactions, research shows that aldehyde oxidase (AOX) could act as a reductase toward Noxides, sulfoxides, and heterocycles under hypoxic conditions (Kitamura and Tatsumi, 1984a,b). It has been demonstrated more recently that AOX can catalyze the hydrolysis of amide bonds (Sodhi et al, 2015). Interest in AOX has increased considerably in recent years, and drug metabolism and pharmacokinetics laboratories have implemented assays to screen for its activity This interest primarily stems from changing chemical-derivation or synthesis trends that, they improve drug properties, may result in clearance by non-P450 pathways. Introduction of groups, such as azaheterocycles, may improve
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
