Guanidino compounds in serum, urine, liver, kidney, and brain of man and some ureotelic animals

doi:10.1016/0026-0495(92)90213-T

Metabolism

Volume 41, Issue 5, May 1992, Pages 526-532

https://doi.org/10.1016/0026-0495(92)90213-T Get rights and content

Abstract

Guanidino compound levels were quantitatively determined in serum, urine, liver, kidney, and brain of man and of some ureotelic animals. The guanidino compounds were separated over a cation exchange resin, using sodium citrate buffers, and detected with the fluorescence ninhydrin method. Species-specific differences in the levels of some guanidino compounds in the studied ureotelic animals are shown. α-Keto-δ-guanidinovaleric acid is a naturally occurring guanidino compound in ureotelic animals, and is not restricted to the pathobiochemistry to hyperargininemic patients. The fasting serum levels observed in beagles are the same as those found in hyperargininemic patients. In serum, liver, and kidney, the homoarginine, β-guanidinopropionic acid, and γ-guanidinobutyric acid levels are the highest in rats. The last two compounds have the highest levels of the studied guanidino compounds, with the exception of creatine, in kidney. Specific high levels of γ-guanidinobutyric acid and argininic acid are found in brain of rabbits.

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Creatine (Cr) is needed to maintain high energy levels in cells. Since Cr plays reportedly a critical role in neurodevelopment and the immune system, Cr dynamics should be strictly regulated to control these physiological events. This review focuses on the role of transporters that recognize Cr and/or Cr precursors. Our previous studies revealed physiological roles of SLC6A and SLC16A family transporters in Cr dynamics. Creatine transporter (CRT/SLC6A8) contributes to the influx transport of Cr in Cr distribution. γ-Aminobutyric acid transporter 2 (GAT2/SLC6A13) mediates incorporation of guanidinoacetate (GAA), a Cr precursor, in the process of Cr biosynthesis. Monocarboxylate transporter 12 (MCT12/SLC16A12) functions as an efflux transporter for Cr and GAA, and contributes to the process of Cr biosynthesis. Accordingly, the SLC6A and SLC16A family of transporters play important roles in the process of Cr biosynthesis and distribution via permeation of Cr and Cr precursors across the plasma membrane.
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The biosynthesis of creatine (Cr) is closely related to the bioavailability of guanidinoacetate (GAA). The lack of one or the other may compromise their role in the energy transport and cell signaling. A reliable estimate of their levels in biological samples is imperative since they are important markers of many metabolic disorders. Therefore, a new LC-MS/MS method for simultaneous determination and quantification of GAA and Cr by multiple reaction monitoring (MRM) mode was developed based on the hydrophilic interaction chromatography (HILIC) and response surface methodology (RSM) for the optimization of chromatographic parameters. The optimized parameters ensured good separation of these similar, very polar molecules (chromatographic resolution > 1.5) without prior derivatization step in a short analysis run (6 min). The developed method was validated to ensure accurate (R, 75.1–101.6%), precise (RSD < 20%) and low quantification (LOQ of 0.025 μg mL⁻¹ for GAA and 0.006 μg mL⁻¹ for Cr) of the tested analytes and the use of matrix-matched calibration eliminated variable effects of complex matrices such as human plasma and urine. Therefore, this method can be implemented in medical laboratories as a tool for the diagnostics of creatine deficiencies and monitoring of guanidinoacetate and creatine supplementation regimes in biological samples.
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Improving efficacy and lowering resistance to metal-based drugs can be addressed by consideration of the coordination complex speciation and key reactions important to vanadium antidiabetic drugs or platinum anticancer drugs under biological conditions. The methods of analyses vary depending on the specific metal ion chemistry. The vanadium compounds interconvert readily, whereas the reactions of the platinum compounds are much slower and thus much easier to study. However, the vanadium species are readily differentiated due to vanadium complexes differing in color. For both vanadium and platinum systems, understanding the processes as the compounds, Lipoplatin and Satraplatin, enter cells is needed to better combat the disease; there are many cellular metabolites, which may affect processing and thus the efficacy of the drugs. Examples of two formulations of platinum compounds illustrate how changing the chemistry of the platinum will result in less toxic and better tolerated drugs. The consequence of the much lower toxicity of the drug, can be readily realized because cisplatin administration requires hospital stay whereas Lipoplatin can be done in an outpatient manner. Similarly, the properties of Satraplatin allow for development of an oral drug. These forms of platinum demonstrate that the direct consequence of more selective speciation is lower side effects and cheaper administration of the anticancer agent. Therefore we urge that as the community goes forward in development of new drugs, control of speciation chemistry will be considered as one of the key strategies in the future development of anticancer drugs.
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4-Epi-oxytetracycline (4-EOTC), one of main oxytetracycline (OTC) metabolites, can be commonly detected in food and environment. The toxicity and effects of OTC on animals have been well characterized; however, its metabolites have never been studied systemically. This study aims to investigate 15-day oral dose toxicity and urine metabonomics changes of 4-EOTC after repeated administration in Wistar rats at daily doses of 0.5, 5.0 and 50.0 mg/kg bw (bodyweight). Hematology and clinical chemistry parameters, including white blood cell count, red blood cell count, total protein, globulin and albumin/globulin, were obviously altered in rats of 5.0 and 50.0 mg/kg bw. Histopathology changes of kidney and liver tissues were also observed in high-dose groups. Urinary metabolites from all groups were analyzed using ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Seventeen metabolites contributing to the clusters were identified as potential biomarkers from multivariate analysis, including aminoadipic acid, 6-phosphogluconate, sebacic acid, pipecolic acid, etc. The significant changes of these biomarkers demonstrated metabonomic variations in treated rats, especially lysine and purine metabolism. For the first time in this paper, we combined the results of toxicity and metabonomics induced by 4-EOTC for the serious reconsideration of the safety and potential risks of antibiotics and its degradation metabolites.
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Citation Excerpt :
This effect has been attributed to the nephropathy caused by the drug [12,13]. Guanidinoacetic acid (Fig. 1b) is significantly involved in renal metabolism, since it is mainly synthesized in the kidneys and subsequently excreted in urine or methylated for creatine production [13,14]. For this reason, GAA is regarded as a more sensitive marker for chronic renal dysfunction [15].
Cisplatin, cis-dichlorodiammineplatinum(II) is one the most employed antineoplasic drugs, exhibiting activity for different types of tumors. Cisplatin resistance can be related to its reduced uptake or retention, causing the decrease of the platinum–DNA adduct. This is attributed to cisplatin binding to other cellular components, causing its deactivation or damage to its normal biochemical pathway. Several studies with a focus on elucidating cisplatin binding to compounds present in cells have been conducted. In the present study, the interaction of cisplatin with one potential O and N-donor ligand, guanidinoacetic acid, was investigated, an amino acid found at high concentrations in the kidney and liver, organs where the drug accumulates. In vitro GAA and cisplatin interaction was studied in aqueous medium at the same ionic strength (0.1 mol L⁻¹ KCl) and temperature (36.5 °C) as fluids of the body. Potentiometric and NMR (¹H and ¹⁹⁵Pt) analyses have been done, with the determination of stability constants and theoretical calculations for the principal structures involved. Results showed that GAA may be one of the potential biomolecules of cisplatin since, under the conditions of temperature and ionic strength of the body at around pH 7, part of cisplatin interacted with GAA to form [Pt(NH₃)₂(HGAA)₂]²⁺. Optimization of this species, [Pt(NH₃)₂(HGAA)₂]²⁺ was carried out using the gaussian 03 package with the B3LYP function in combination with LANL2DZ (6–311G(d,p)), yielding a planar sphere coordination around Pt(II) and also O–H intramolecular interactions in the complex. The results on speciation for cisplatin/GAA systems could be of great interest since GAA may be one of the potential binding species of cisplatin, especially in the study of 5:1 cisplatin/GAA ratio (found in rats, for example).
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Objective: To determine the prognostic factors for encephalopathy with bright tree appearance (BTA) in the acute phase through retrospective case evaluation. Methods: We recruited 10 children with encephalopathy who presented with BTA and classified them into 2 groups. Six patients with evident regression and severe psychomotor developmental delay after encephalopathy were included in the severe group, while the remaining 4 patients with mild mental retardation were included in the mild group. We retrospectively analyzed their clinical symptoms, laboratory data, and magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) findings. Results: Patients in the severe group developed subsequent complications such as epilepsy and severe motor impairment. Univariate analysis revealed that higher maximum lactate dehydrogenase (LDH) levels (p = 0.055) were a weak predictor of poor outcome. Maximum creatinine levels were significantly higher (p < 0.05) and minimal platelet counts were significantly lower (p < 0.05) in the severe group than in the mild group. Acute renal failure was not observed in any patient throughout the study. MRS of the BTA lesion during the BTA period showed elevated lactate levels in 5 children in the severe group and 1 child in the mild group. MRI performed during the chronic phase revealed severe brain atrophy in all patients in the severe group. Conclusions: Higher creatinine and LDH levels and lower platelet counts in the acute phase correlated with poor prognosis. Increased lactate levels in the BTA lesion during the BTA period on MRS may predict severe physical and mental disability.

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^☆: Supported by the “Ministerie van Nationale Opvoeding en Nederlandse Cultuur,” the University of Antwerp, the Born Bunge Foundation, the United Fund of Belgium, Medical Research Council Canada (I.A.Q.), and Grant No. AI 20236-07 and a Research Career Development Award (D.R.D.) from the National Institutes of Health.

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Guanidino compounds in serum, urine, liver, kidney, and brain of man and some ureotelic animals☆

Abstract

J Biol Chem

Anal Biochem

Microchem J

Clin Chim Acta

J Chromatogr

J Biol Chem

Biochim Biophys Acta

Biochim Biophys Acta

J Biol Chem

J Biol Chem

Arch Biochem Biophys

Am J Med

Natural guanidino compounds

Guanidinederivaten: Metabool-biochemisch, diagnostisch, therapeutisch en pathofysiologisch belang

The distribution of arginine between plasma and cells

Sur la composition chimique du bouillon de viande

J Pharm Chim (Paris)

Vorläufige Notiz über einen neuen stickstoffhaltigen Körper im Harne

Liebigs Ann Chem

The presence of glycocyamine in urine

A case of hyperlysinemia: Biochemical and clinical observations

Pediatrics

Occurrence of guanidinoacetic acid and other substituted guanidines in mammalian liver

Biochem J