Journal article
In vitro oxidative metabolism of 6-mercaptopurine in human liver: insights into the role of the molybdoflavoenzymes aldehyde oxidase, xanthine oxidase, and xanthine dehydrogenase
Drug metabolism and disposition, Vol.42(8), pp.1334-1340
08/2014
Handle:
https://hdl.handle.net/2376/107317
PMCID: PMC4109211
PMID: 24824603
Abstract
Anticancer agent 6-mercaptopurine (6MP) has been in use since 1953 for the treatment of childhood acute lymphoblastic leukemia (ALL) and inflammatory bowel disease. Despite being available for 60 years, several aspects of 6MP drug metabolism and pharmacokinetics in humans are unknown. Molybdoflavoenzymes such as aldehyde oxidase (AO) and xanthine oxidase (XO) have previously been implicated in the metabolism of this drug. In this study, we investigated the in vitro metabolism of 6MP to 6-thiouric acid (6TUA) in pooled human liver cytosol. We discovered that 6MP is metabolized to 6TUA through sequential metabolism via the 6-thioxanthine (6TX) intermediate. The role of human AO and XO in the metabolism of 6MP was established using the specific inhibitors raloxifene and febuxostat. Both AO and XO were involved in the metabolism of the 6TX intermediate, whereas only XO was responsible for the conversion of 6TX to 6TUA. These findings were further confirmed using purified human AO and Escherichia coli lysate containing expressed recombinant human XO. Xanthine dehydrogenase (XDH), which belongs to the family of xanthine oxidoreductases and preferentially reduces nicotinamide adenine dinucleotide (NAD(+)), was shown to contribute to the overall production of the 6TX intermediate as well as the final product 6TUA in the presence of NAD(+) in human liver cytosol. In conclusion, we present evidence that three enzymes, AO, XO, and XDH, contribute to the production of 6TX intermediate, whereas only XO and XDH are involved in the conversion of 6TX to 6TUA in pooled HLC.
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- Title
- In vitro oxidative metabolism of 6-mercaptopurine in human liver: insights into the role of the molybdoflavoenzymes aldehyde oxidase, xanthine oxidase, and xanthine dehydrogenase
- Creators
- Kanika V Choughule - Department of Chemistry, Washington State University, Pullman, WashingtonCarlo Barnaba - Department of Chemistry, Washington State University, Pullman, WashingtonCarolyn A Joswig-Jones - Department of Chemistry, Washington State University, Pullman, WashingtonJeffrey P Jones - Department of Chemistry, Washington State University, Pullman, Washington jpj@wsu.edu
- Publication Details
- Drug metabolism and disposition, Vol.42(8), pp.1334-1340
- Academic Unit
- Chemistry, Department of
- Publisher
- United States
- Grant note
- R01 GM100874 / NIGMS NIH HHS GM100874 / NIGMS NIH HHS
- Identifiers
- 99900547021801842
- Language
- English
- Resource Type
- Journal article