Neopterin formation through radical scavenging of superoxide by the macrophage synthesised antioxidant 7,8-dihydroneopterin.

Baxter-Parker G; Prebble HM; Cross S; Steyn N; Shchepetkina A; Hock BD; Cousins A; Gieseg SP

doi:10.1016/j.freeradbiomed.2020.03.002

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Journal article

Neopterin formation through radical scavenging of superoxide by the macrophage synthesised antioxidant 7,8-dihydroneopterin.

Baxter-Parker G Free Radical Biochemistry, School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.
Prebble HM Free Radical Biochemistry, School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.
Cross S Free Radical Biochemistry, School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.
Steyn N Free Radical Biochemistry, School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.
Shchepetkina A Free Radical Biochemistry, School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.
Hock BD Haematology Research, Department of Pathology and Biomedical Sciences, University of Otago Christchurch, New Zealand.
Cousins A Department of Medical Physics and Bioengineering, Christchurch Hospital, Canterbury District Health Board, New Zealand.
Gieseg SP Free Radical Biochemistry, School of Biological Sciences, University of Canterbury, Christchurch, New Zealand; Department of Radiology, University of Otago Christchurch, New Zealand; European Organization for Nuclear Research (CERN), Geneva, Switzerland. Electronic address: Steven.Gieseg@canterbury.ac.nz.

2020-03-08

Published in:

Free radical biology & medicine. - 2020

English Clinical measurement of neopterin has been extensively used as a marker of inflammation but the in vivo mechanism generating neopterin is poorly understood. Neopterin is described as the oxidation product of 7,8-dihydroneopterin, a potent antioxidant generated by monocyte/macrophages in response to interferon-γ. While peroxyl and hydroxyl scavenging generates dihydroxanthopterin, hypochlorite efficiently oxidises 7,8-dihydroneopterin into neopterin, but this reaction alone does not explain the high levels of neopterin seen in clinical data. Here, we examine whether superoxide scavenging by 7,8-dihydroneopterin generates neopterin. U937 cells incubated with oxLDL showed a time dependent increase superoxide and 7,8-dihydroneopterin oxidation to neopterin. Neopterin generation in oxLDL or phorbol ester treated U937 cells or human monocytes was inhibited by apocynin and PEG-SOD. Addition of the myeloperoxidase inhibitor 4-aminobenzoic acid hydrazide (ABAH) had no effect of the superoxide generation or neopterin formation. 7,8-Dihydroneopterin reacted with superoxide/hydroxy radical mixtures generated by X-ray radiolysis to give neopterin. Formation of neopterin by superoxide derived from the xanthine/xanthine oxidase system was inhibited by superoxide dismutase. Neopterin formation was inhibited by apocynin in phorbol ester treated human carotid plaque rings in tissue culture. These results indicate that 7,8-dihydroneopterin scavenges superoxide and is subsequently oxidised into neopterin in cellular and cell-free experimental systems.

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