Please use this identifier to cite or link to this item: http://docs.prosentient.com.au/prosentientjspui/handle/1/10204
Title: Impaired systemic tetrahydrobiopterin bioavailability and increased dihydrobiopterin in adult falciparum malaria: association with disease severity, impaired microvascular function and increased endothelial activation.
Authors: Yeo, Tsin W
Lampah, Daniel A
Kenangalem, Enny
Tjitra, Emiliana
Price, Ric N
Weinberg, J Brice
Hyland, Keith
Granger, Donald L
Anstey, Nicholas M
Affiliation: Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Institute of Infectious Disease and Epidemiology, Tan Tock Seng Hospital, Singapore..
Menzies School of Health Research-National Institute of Health Research and Development Research Program, and District Ministry of Health, Timika, Papua, Indonesia..
Menzies School of Health Research-National Institute of Health Research and Development Research Program, and District Ministry of Health, Timika, Papua, Indonesia..
National Institute of Health Research and Development, Jakarta, Indonesia..
Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom..
Duke University and VA Medical Centers, Durham, North Carolina, United States of America..
Medical Neurogenetics LLC, Atlanta, Georgia, United States of America..
Division of Infectious Diseases, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, United States of America..
Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia; Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia..
Issue Date: Mar-2015
Citation: PLoS pathogens 2015-03; 11(3): e1004667
Abstract: Tetrahydrobiopterin (BH₄) is a co-factor required for catalytic activity of nitric oxide synthase (NOS) and amino acid-monooxygenases, including phenylalanine hydroxylase. BH4 is unstable: during oxidative stress it is non-enzymatically oxidized to dihydrobiopterin (BH₂), which inhibits NOS. Depending on BH₄ availability, NOS oscillates between NO synthase and NADPH oxidase: as the BH₄/BH₂ ratio decreases, NO production falls and is replaced by superoxide. In African children and Asian adults with severe malaria, NO bioavailability decreases and plasma phenylalanine increases, together suggesting possible BH₄ deficiency. The primary three biopterin metabolites (BH₄, BH₂ and B₀ [biopterin]) and their association with disease severity have not been assessed in falciparum malaria. We measured pterin metabolites in urine of adults with severe falciparum malaria (SM; n=12), moderately-severe malaria (MSM, n=17), severe sepsis (SS; n=5) and healthy subjects (HC; n=20) as controls. In SM, urinary BH₄ was decreased (median 0.16 ¼mol/mmol creatinine) compared to MSM (median 0.27), SS (median 0.54), and HC (median 0.34)]; p<0.001. Conversely, BH₂ was increased in SM (median 0.91 ¼mol/mmol creatinine), compared to MSM (median 0.67), SS (median 0.39), and HC (median 0.52); p<0.001, suggesting increased oxidative stress and insufficient recycling of BH2 back to BH4 in severe malaria. Overall, the median BH₄/BH₂ ratio was lowest in SM [0.18 (IQR: 0.04-0.32)] compared to MSM (0.45, IQR 0.27-61), SS (1.03; IQR 0.54-2.38) and controls (0.66; IQR 0.43-1.07); p<0.001. In malaria, a lower BH₄/BH₂ ratio correlated with decreased microvascular reactivity (r=0.41; p=0.03) and increased ICAM-1 (r=-0.52; p=0.005). Decreased BH4 and increased BH₂ in severe malaria (but not in severe sepsis) uncouples NOS, leading to impaired NO bioavailability and potentially increased oxidative stress. Adjunctive therapy to regenerate BH4 may have a role in improving NO bioavailability and microvascular perfusion in severe falciparum malaria.
URI: http://docs.prosentient.com.au/prosentientjspui/handle/1/10204
DOI: 10.1371/journal.ppat.1004667
Type: Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Subjects: Adult
Biopterin
Creatinine
Endothelium
Female
Humans
Malaria, Falciparum
Male
Nitric Oxide
Sepsis
Severity of Illness Index
Microcirculation
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