Establishment of the Process in Blood Sampling and Sample Handling as a Biomarker of Hypoxia-Inducible Diseases; Plasma Hypoxanthine and Xanthine Measurement

Nakamura, Takashi; Murase, Takayo; Satoh, Etsuko; Hibi, Chihiro; Nakayama, Yukiharu; Katoh, Noriaki; Yokoyama, Hiroaki; Tomita, Hirofumi

doi:10.4172/2155-9929.1000404

Cited by 8 publications

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“…It has been reported that the tissue content of hypoxanthine in human adipose tissue is higher than the contents of xanthine and uric acid, and that human fat tissue mainly produces hypoxanthine among purine catabolism‐related metabolites. In a condition of hypoxia, adenosine triphosphate is degraded to hypoxanthine through adenosine diphosphate, adenosine monophosphate, adenosine and inosine, and hypoxanthine, a nucleobase, is secreted from cells through several transporters, including equilibrative nucleobase transporter 1 and equilibrative nucleoside transporters. It has also been shown that hypoxia increases the production of hypoxanthine in human adipocytes.…”

Section: Discussionmentioning

confidence: 99%

“…In our population‐based cohort, the Tanno‐Sobetsu Study, 605 Japanese individuals (men/women: 280/325) of Sobetsu Town underwent annual examinations in 2017. Among them, 121 individuals (men/women: 56/65) were excluded, as the time until blood processing of centrifugal plasma separation was >3 h, which might affect concentrations of hypoxanthine and xanthine by leakage from erythrocytes. A total of 484 individuals (men/women: 224/260) were enrolled in the present study.…”

Section: Methodsmentioning

confidence: 99%

“…For plasma separation, the samples were centrifuged at 2,000 g for 10 min at 4°C. Plasma concentrations of xanthine and hypoxanthine were determined as previously reported. In brief, plasma samples were added to methanol containing [ 13 C 2 , 15 N 2 ] xanthine and [ 13 C 3 , 15 N] hypoxanthine as internal controls, and were centrifuged at 3,000 g for 15 min at 4°C.…”

Section: Methodsmentioning

confidence: 99%

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Differential regulation of hypoxanthine and xanthine by obesity in a general population

Furuhashi

Koyama

Higashiura

et al. 2020

J of Diabetes Invest

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Aims/Introduction: Uric acid is synthesized by oxidation of hypoxanthine and xanthine using a catalyzing enzyme, xanthine oxidoreductase (XOR), which can be a source of reactive oxygen species. Plasma XOR activity is a metabolic biomarker associated with obesity, hyperuricemia, liver dysfunction and insulin resistance. However, it has recently been reported that XOR activity in fat tissue is low in humans, unlike in rodents, and that hypoxanthine is secreted from human fat tissue. Materials and Methods: The associations of obesity with hypoxanthine, xanthine and plasma XOR activity were investigated in 484 participants (men/women: 224/260) of the Tanno-Sobetsu Study. Results: Levels of hypoxanthine, xanthine and plasma XOR activity were significantly higher in men than in women. In 59 participants with hyperuricemia, 11 (men/women: 11/0) participants were being treated with an XOR inhibitor and had a significantly higher level of xanthine, but not hypoxanthine, than that in participants without treatment. In all of the participants, hypoxanthine concentration in smokers was significantly higher than that in non-smokers. Stepwise and multivariate regression analyses showed that body mass index, smoking habit and xanthine were independent predictors of hypoxanthine after adjustment of age, sex and use of antihyperuricemic drugs. Whereas, alanine transaminase, hypoxanthine and plasma XOR activity were independent predictors for xanthine, and alanine transaminase, triglycerides and xanthine were independent predictors for plasma XOR activity. Conclusions: The concentration of hypoxanthine, but not that of xanthine, is independently associated with obesity and smoking habit, indicating differential regulation of hypoxanthine and xanthine in a general population.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Differential regulation of hypoxanthine and xanthine by obesity in a general population

Furuhashi

Koyama

Higashiura

et al. 2020

J of Diabetes Invest

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“…Blood samples were collected from the patients using PAX gene Blood DNA tubes (Becton, Dickinson and Company, Japan.) in the fasting condition early in the morning, and then centrifuged at 3000 rpm for 10 min at 4 °C within 8 h after blood collection to avoid the leak of hypoxanthine and xanthine from erythrocytes into the plasma [30]. The supernatant plasma samples were maintained at -80 °C until the assay.…”

Section: Blood Sampling and Measurement Of The Plasma Xor Activity Xmentioning

confidence: 99%

“…The lower limit of detection was 6.67 pmol/h/mL plasma, and intra-and inter-assay coefficients of variation were 6.5% and 9.1%, respectively. Plasma hypoxanthine and xanthine were also measured as previously reported [30,31]. In brief, plasma samples were added into methanol containing [13C2, 15N2] xanthine and [13C3, 15N] hypoxanthine as internal standard and were centrifuged by 3,000 g at 4 °C for 15 min.…”

Section: Blood Sampling and Measurement Of The Plasma Xor Activity Xmentioning

confidence: 99%

Association of the plasma xanthine oxidoreductase activity with the metabolic parameters and vascular complications in patients with type 2 diabetes: a cross-sectional study in a hospital setting

Okuyama

Shirakawa

Nakamura

et al. 2020

Preprint

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Background Xanthine oxidoreductase (XOR) is a rate-limiting enzyme that catalyzes the oxidation of hypoxanthine to xanthine, and of xanthine to uric acid. XOR also enhances the production of reactive oxygen species (ROS) and causes endothelial dysfunction. To explore the association of XOR and its substrate with the vascular complications in patients with type 2 diabetes mellitus (hereafter simply, diabetes), we measured the plasma XOR activity and plasma levels of xanthine and hypoxanthine in patients with type 2 diabetes. Materials and Methods Plasma XOR activity and the plasma levels of xanthine and hypoxanthine were measured, and their associations with the clinical parameters and vascular complications were investigated in 94 Japanese inpatients with type 2 diabetes. Results Both the plasma XOR activity and plasma xanthine levels were correlated with the serum uric acid level. The plasma XOR activity was correlated with the plasma xanthine level, but not the plasma hypoxanthine level. The plasma XOR activity and plasma xanthine levels were positively correlated with the body mass index (BMI), serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum γ-GTP, fasting plasma insulin, and the homeostasis model of assessment of insulin resistance (HOMA-IR), and negatively correlated with the serum high density lipoprotein cholesterol levels (HDL-C). The plasma XOR activity also showed a positive correlation with the serum triglyceride (TG) levels. Plasma xanthine was positively correlated with the Fib4-index. Multivariate analyses identified AST, ALT, fasting plasma insulin and HOMA-IR as being independently associated with the plasma XOR activity. In addition, a negative correlation was observed between the plasma XOR activity and the duration of diabetes, and positive correlations were observed between the plasma XOR activity and the coefficient of variation of the R-R interval (CVR-R) and sensory nerve conduction velocity (SCV). Furthermore, the plasma XOR activity was found to be significantly decreased in patients with coronary artery disease. Conclusions The plasma XOR activity might be a surrogate marker for the development of vascular complications, as well as liver dysfunction and insulin resistance, in patients with type 2 diabetes

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Association of the plasma xanthine oxidoreductase activity with the metabolic parameters and vascular complications in patients with type 2 diabetes

Okuyama

Shirakawa

Nakamura

et al. 2021

Sci Rep

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Xanthine oxidoreductase (XOR) catalyzes the oxidation of hypoxanthine to xanthine, and of xanthine to uric acid. XOR also enhances the production of reactive oxygen species and causes endothelial dysfunction. In this study, we evaluated the association of XOR and its substrate with the vascular complications in 94 Japanese inpatients with type 2 diabetes (T2DM). The plasma XOR activity and plasma xanthine levels were positively correlated with the body mass index, aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-GTP, fasting plasma insulin, and the homeostasis model of assessment of insulin resistance (HOMA-IR), and negatively correlated with the high density lipoprotein cholesterol. The plasma XOR activity also showed a positive correlation with the serum triglyceride. Multivariate analyses identified AST, ALT, fasting plasma insulin and HOMA-IR as being independently associated with the plasma XOR activity. The plasma XOR activity negatively correlated with the duration of diabetes, and positively correlated with the coefficient of variation of the R-R interval and sensory nerve conduction velocity. Furthermore, the plasma XOR activity was significantly decreased in patients with coronary artery disease. Thus, the plasma XOR activity might be a surrogate marker for the development of vascular complications, as well as liver dysfunction and insulin resistance, in T2DM.Trial registration: This study is registered at the UMIN Clinical Trials Registry (UMIN000029970; https://www.umin.ac.jp/ctr/index-j.htm). The study was conducted from Nov 15, 2017.

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Establishment of the Process in Blood Sampling and Sample Handling as a Biomarker of Hypoxia-Inducible Diseases; Plasma Hypoxanthine and Xanthine Measurement

Cited by 8 publications

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Differential regulation of hypoxanthine and xanthine by obesity in a general population

Differential regulation of hypoxanthine and xanthine by obesity in a general population

Association of the plasma xanthine oxidoreductase activity with the metabolic parameters and vascular complications in patients with type 2 diabetes: a cross-sectional study in a hospital setting

Association of the plasma xanthine oxidoreductase activity with the metabolic parameters and vascular complications in patients with type 2 diabetes

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