In vitro study of 6-mercaptopurine oxidation catalysed by aldehyde oxidase and xanthine oxidase.
In spite of over 40 years of clinical use of 6-mercaptopurine, many aspects of complex pharmacology and metabolism of this drug remain unclear. It is thought that 6-mercaptopurine is oxidized to 6-thiouric acid through 6-thioxanthine or 8-oxo-6-mercaptopurine by one of two molybdenum hydroxylases, xanthine oxidase (XO), however, the role of other molybdenum hydroxylase, aldehyde oxidase (AO), in the oxidation of 6-mercaptopurine and possible interactions of AO substrates and inhibitors has not been investigated in more details. In the present study, the role of AO and XO in the oxidation of 6- mercaptopurine has been investigated. 6-mercaptopurine was incubated with bovine milk xanthine oxidase or partially purified guinea pig liver molybdenum hydroxylase fractions in the absence and presence of XO and AO inhibitor/substrates, and the reactions were monitored by spectrophotometric and HPLC methods. According to the results obtained from the inhibition studies, it is more likely that 6- mercaptopurine is oxidized to 6-thiouric acid via 6-thioxanthine rather than 8-oxo-6-mercaptopurine. The first step which is the rate limiting step is catalyzed solely by XO, whereas both XO and AO are involved in the oxidation of 6-thioxanthine to 6-thiouric acid.
Rashidi
Mohammad-Reza
MR
Drug Applied Research Center, Research and Development Complex, Tabriz University of Medical Sciences, Iran. rashidi@tbzmed.ac.ir
Beedham
Christine
C
Smith
John S
JS
Davaran
Soodabeh
S
D042931:Aldehyde Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000963:Antimetabolites / Q000378:metabolism*; D002384:Catalysis; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D015122:Mercaptopurine / Q000378:metabolism*; D008892:Milk / Q000201:enzymology; D010084:Oxidation-Reduction; D013056:Spectrophotometry, Ultraviolet; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*