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Issue 9, 2021

Thioguanine restoration through type I photosensitization-superoxide oxidation-glutathione reduction cycles

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Abstract

UVA-induced deleterious effect of thiopurine prodrugs including azathioprine, 6-mercaptopurine and 6-thioguanine (6-TG) increases the risk of cancer development due to the incorporation of 6-TG in patients’ DNA. The catalytic mechanism by which thiobases act as a sustained oxidant producer has yet to be explored, especially through the Type I electron transfer pathway that produces superoxide radicals (O2˙). Under Fenton-like conditions O2˙ radicals convert to extremely reactive hydroxyl radicals (˙OH), thus carrying even higher risk of biological damage than that induced by the well-studied type II reaction. By monitoring 6-TG/UVA-induced photochemistry in mass spectra and superoxide radicals (O2˙) via nitro blue tetrazolium (NBT) reduction, this work provides two new findings: (1) in the presence of reduced glutathione (GSH), the production of O2˙via the type I reaction is enhanced 10-fold. 6-TG thiyl radicals are identified as the primary intermediate formed in the reaction of 6-TG with O2˙. The restoration of 6-TG and concurrent generation of O2˙ occur via a 3-step-cycle: 6-TG type I photosensitization, O2˙ oxidation and GSH reduction. (2) In the absence of GSH, 6-TG thiyl radicals undergo oxygen addition and sulfur dioxide removal to form carbon radicals (C6) which further convert to thioether by reacting with 6-TG molecules. These findings help explain not only thiol-regulation in a biological system but chemoprevention of cancer.

Graphical abstract: Thioguanine restoration through type I photosensitization-superoxide oxidation-glutathione reduction cycles

Supplementary files

Article information


Submitted
08 Jan 2021
Accepted
25 Feb 2021
First published
25 Feb 2021

Phys. Chem. Chem. Phys., 2021,23, 5069-5073
Article type
Communication

Thioguanine restoration through type I photosensitization-superoxide oxidation-glutathione reduction cycles

N. Euceda, J. Jahnke, A. Espinal, M. F. Louis, E. Bashkin, P. Roccanova, A. Espaillat, G. V. Fuentes, F. Nieto and R. Gao, Phys. Chem. Chem. Phys., 2021, 23, 5069 DOI: 10.1039/D1CP00101A

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