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Nabuchi, Yoshiaki; Fujiwara, Eri; Ueno, Kenjyu; Kuboniwa, Hitoshi; Asoh, Yoshinori; Ushio, Hidetoshi

doi:10.1023/a:1016281031373

Cited by 55 publications

(15 citation statements)

References 13 publications

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“…There is overwhelming evidence that oxPTH and n-oxPTH have completely different biological properties [8,9,10,11,12,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48]. Initial studies using classical receptor binding assays demonstrated that oxidized PTH does not bind to the PTH receptor anymore [24,25,26,28,38].…”

Section: Discussionmentioning

confidence: 99%

“…Initial studies using classical receptor binding assays demonstrated that oxidized PTH does not bind to the PTH receptor anymore [24,25,26,28,38]. Other studies focused on the generation of the second messenger of PTH-receptor, cAMP These studies indicated that oxidized PTH - in contrast to non-oxidized PTH - does not stimulate the PTH receptor to generate cAMP [9,24,25,37,42,45,48]. In addition, it was demonstrated that oxidized PTH loses its biological action on smooth muscle cells contraction/vascular effects in tissues like trachea, and aortic rings, and uterus [32,35,36,41,42,45].…”

Section: Discussionmentioning

confidence: 99%

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Modeling of Oxidized PTH (oxPTH) and Non-oxidized PTH (n-oxPTH) Receptor Binding and Relationship of Oxidized to Non-Oxidized PTH in Children with Chronic Renal Failure, Adult Patients on Hemodialysis and Kidney Transplant Recipients

Hocher

Oberthür

Slowinski

et al. 2013

Kidney Blood Press Res

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Background: The biological properties of oxidized and non-oxidized PTH are substantially different. Oxidized PTH (oxPTH) loses its PTH receptor-stimulating properties, whereas non-oxidized PTH (n-oxPTH) is a full agonist of the receptor. This was described in more than 20 well published studies in the 1970^s and 80^s. However, PTH oxidation has been ignored during the development of PTH assays for clinical use so far. Even the nowadays used third generation assay systems do not consider oxidation of PTH We recently developed an assay to differentiate between oxPTH and n-oxPTH. In the current study we established normal values for this assay system. Furthermore, we compare the ratio of oxPTH to n-oxPTH in different population with chronic renal failure: 620 children with renal failure stage 2-4 of the 4C study, 342 adult patients on dialysis, and 602 kidney transplant recipients. In addition, we performed modeling of the interaction of either oxPTH or n-oxPTH with the PTH receptor using biophysical structure approaches. Results: The children had the highest mean as well as maximum n-oxPTH concentrations as compared to adult patients (both patients on dialysis as well as kidney transplant recipients). The relationship between oxPTH and n-oxPTH of individual patients varied substantially in all three populations with renal impairment. The analysis of n-oxPTH in 89 healthy control subjects revealed that n-oxPTH concentrations in patient with renal failure were higher as compared to healthy adult controls (2.25-fold in children with renal failure, 1.53-fold in adult patients on dialysis, and 1.56-fold in kidney transplant recipients, respectively). Computer assisted biophysical structure modeling demonstrated, however, minor sterical- and/or electrostatic changes in oxPTH and n-oxPTH. This indicated that PTH oxidation may induce refolding of PTH and hence alters PTH-PTH receptor interaction via oxidation induced three-dimensional structure alteration of PTH. Conclusion: A huge proportion of circulating PTH measured by current state-of-the-art assay systems is oxidized and thus not biologically active. The relationship between oxPTH and n-oxPTH of individual patients varied substantially. Non-oxidized PTH concentrations are 1.5 - 2.25 fold higher in patients with renal failure as compared to health controls. Measurements of n-oxPTH may reflect the hormone status more precise. The iPTH measures describes most likely oxidative stress in patients with renal failure rather than the PTH hormone status. This, however, needs to be demonstrated in further clinical studies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Modeling of Oxidized PTH (oxPTH) and Non-oxidized PTH (n-oxPTH) Receptor Binding and Relationship of Oxidized to Non-Oxidized PTH in Children with Chronic Renal Failure, Adult Patients on Hemodialysis and Kidney Transplant Recipients

Hocher

Oberthür

Slowinski

et al. 2013

Kidney Blood Press Res

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“…Similarly, Gitlin and colleagues (22) established that oxidation of Met-111 in interferon ␣-2b did not alter its biological activity. Nabuchi et al (23) reported studies on hydrogen peroxide-mediated oxidation of the two methionine residues present in human parathyroid hormone. Oxidation of Met-8 slightly reduced biological activity, whereas oxidation of Met-18 substantially reduced activity.…”

Section: Discussionmentioning

confidence: 99%

Methionine residues as endogenous antioxidants in proteins

Levine

Mosoni

Berlett

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

973

755

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Cysteine and methionine are the two sulfurcontaining residues normally found in proteins. Cysteine residues function in the catalytic cycle of many enzymes, and they can form disulfide bonds that contribute to protein structure. In contrast, the specific functions of methionine residues are not known. We propose that methionine residues constitute an important antioxidant defense mechanism. A variety of oxidants react readily with methionine to form methionine sulfoxide, and surface exposed methionine residues create an extremely high concentration of reactant, available as an efficient oxidant scavenger. Reduction back to methionine by methionine sulfoxide reductases would allow the antioxidant system to function catalytically. The effect of hydrogen peroxide exposure upon glutamine synthetase from Escherichia coli was studied as an in vitro model system. Eight of the 16 methionine residues could be oxidized with little effect on catalytic activity of the enzyme. The oxidizable methionine residues were found to be relatively surface exposed, whereas the intact residues were generally buried within the core of the protein. Furthermore, the susceptible residues were physically arranged in an array that guarded the entrance to the active site.

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“…Separation, characterization and biological activity of PTH oxidized at methionine 8 and methionine 18 were studied by Frelinger and Zulls [17] . PTH was oxidized with hydrogen peroxide and the biological activity of oxidation products was studied by Nabuchi et al [18] .…”

Section: Introductionmentioning

confidence: 99%

Development and validation of RP-HPLC and RP-UPLC methods for quantification of parathyroid hormones (1-34) in medicinal product formulated with meta-cresol

Rane

Ajameri

Mody

et al. 2012

Journal of Pharmaceutical Analysis

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Rapid and sensitive reversed phase high performance liquid chromatography (RP-HPLC) and ultra performance liquid chromatography (RP-UPLC) method with UV detection has been developed and validated for quantification of parathyroid hormone (PTH) in presence of meta-cresol as a stabilizer in a pharmaceutical formulation. Chromatography was performed with mobile phase containing 0.1% Trifluoroacetic acid (TFA) in MilliQ water and 0.1% TFA in acetonitrile with gradient program and flow rate at 0.3 mL/min for HPLC and 0.4 mL/min for UPLC. Quantification was accomplished with internal reference standard (qualified against innovator product and National Institute for Biological Standards and Control (NIBSC) standard). The methods were validated for linearity (correlation coefficient=0.99), range, accuracy, precision and robustness. Robustness was confirmed by considering three factors; mobile phase composition, column temperature and flow rate/age of mobile phase.Intermediate precision was confirmed on different equipments, different columns and on different days. The relative standard deviation (RSD) (<2% for RP-HPLC and <1% for UPLC, n=30) indicated a good precision. Retention time was found about 17 min and 2 min by HPLC and UPLC methods, respectively. Both methods are simple, highly sensitive, precise and accurate and have the potential of being useful for routine quality control.

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Abstract: The region around Met8 is important for the activity of the parathyroid hormone.

Cited by 55 publications

References 13 publications

Modeling of Oxidized PTH (oxPTH) and Non-oxidized PTH (n-oxPTH) Receptor Binding and Relationship of Oxidized to Non-Oxidized PTH in Children with Chronic Renal Failure, Adult Patients on Hemodialysis and Kidney Transplant Recipients

Modeling of Oxidized PTH (oxPTH) and Non-oxidized PTH (n-oxPTH) Receptor Binding and Relationship of Oxidized to Non-Oxidized PTH in Children with Chronic Renal Failure, Adult Patients on Hemodialysis and Kidney Transplant Recipients

Methionine residues as endogenous antioxidants in proteins

Development and validation of RP-HPLC and RP-UPLC methods for quantification of parathyroid hormones (1-34) in medicinal product formulated with meta-cresol

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