Background & Aims: Hyperammonemia is a frequent side-effect of valproic acid (VPA) therapy, which points to an imbalance between ammoniagenesis and ammonia disposal via the urea cycle. The impairment of this liver-specific metabolic pathway induced either by primary genetic defects or by secondary causes, namely associated with drugs administration, may result in accumulation of ammonia. To elucidate the mechanisms which underlie VPA-induced hyperammonemia, the aim of this study was to evaluate the effect of both VPA and its reactive intermediate, valproyl-CoA (VP-CoA), on the synthesis of N-acetylglutamate (NAG), a prime metabolite activator of the urea cycle.
Methods: The amount of NAG in livers of rats treated with VPA was quantified by HPLC-MS/MS. The NAG synthase (NAGS) activity was evaluated in vitro in rat liver mitochondria, and the effect of both VPA and VP-CoA was characterized.
Results: The present results clearly show that VP-CoA is a stronger inhibitor of NAGS activity in vitro than the parent drug VPA. The hepatic levels of NAG were significantly reduced in VPA-treated rats as compared with control tissues.
Conclusions: These data strongly suggest that the hyperammonemia observed in patients under VPA treatment may result from a direct inhibition of the NAGS activity by VP-CoA. The subsequent reduced availability of NAG will impair the flux through the urea cycle and compromise the major role of this pathway in ammonia detoxification.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.jhep.2010.11.031 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The coupling effect and ecological risk assessment of iron, manganese, and arsenic in the water environment of the central Yangtze River Basin, China.
Environ Geochem Health
December 2024
Hainan Key Laboratory for Coastal Marine Eco-environment and Carbon Sink/ Yazhou Bay Innovation Institute/College of Ecology and Environment, Hainan Tropical Ocean University, Sanya, 572022, Hainan, China.
Excessive heavy metal in drinking water are harmful to human body. Groundwater was still the drinking water resource in most of rural areas in the central of the Yangtze River Basin. Heavy metals of Fe, Mn, and As in the low plain region of the Yangtze River Basin significantly exceeded the standard, resulting in 16.
View Article and Find Full Text PDFMolecular identification of hyaluronate lyase, not hyaluronidase, as an intrinsic hyaluronan-degrading enzyme in Clostridium perfringens strain ATCC 13124.
Sci Rep
October 2024
Laboratory of Basic and Applied Molecular Biotechnology, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto, 611-0011, Japan.
Clostridium perfringens, an opportunistic pathogen, produces mu-toxin hyaluronidases including endo-β-N-acetylglucosaminidases (Nags) as a virulence invasion factor. To clarify an intrinsic factor for degradation of host extracellular hyaluronan, we focused on hyaluronate lyase (HysA), distinct from endo-β-N-acetylglucosaminidases. C.
View Article and Find Full Text PDFPro-CRISPR PcrIIC1-associated Cas9 system for enhanced bacterial immunity.
Nature
June 2024
Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
The CRISPR system is an adaptive immune system found in prokaryotes that defends host cells against the invasion of foreign DNA. As part of the ongoing struggle between phages and the bacterial immune system, the CRISPR system has evolved into various types, each with distinct functionalities. Type II Cas9 is the most extensively studied of these systems and has diverse subtypes.
View Article and Find Full Text PDFCellular landscape of adrenocortical carcinoma at single-nuclei resolution.
Mol Cell Endocrinol
September 2024
Institute of Metabolism and System Research, University of Birmingham, Birmingham, B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism (CEDAM), Birmingham Health Partners, Birmingham, B15 2GW, UK. Electronic address:
Adrenocortical carcinoma (ACC) is a rare yet devastating tumour of the adrenal gland with a molecular pathology that remains incompletely understood. To gain novel insights into the cellular landscape of ACC, we generated single-nuclei RNA sequencing (snRNA-seq) data sets from twelve ACC tumour samples and analysed these alongside snRNA-seq data sets from normal adrenal glands (NAGs). We find the ACC tumour microenvironment to be relatively devoid of immune cells compared to NAG tissues, consistent with known high tumour purity values for ACC as an immunologically "cold" tumour.
View Article and Find Full Text PDFUse of pure recombinant human enzymes to assess the disease-causing potential of missense mutations in urea cycle disorders, applied to N-acetylglutamate synthase deficiency.
J Inherit Metab Dis
November 2024
Instituto de Biomedicina de Valencia, IBV-CSIC, Valencia, Spain.
N-acetylglutamate synthase (NAGS) makes acetylglutamate, the essential activator of the first, regulatory enzyme of the urea cycle, carbamoyl phosphate synthetase 1 (CPS1). NAGS deficiency (NAGSD) and CPS1 deficiency (CPS1D) present identical phenotypes. However, they must be distinguished, because NAGSD is cured by substitutive therapy with the N-acetyl-L-glutamate analogue N-carbamyl-L-glutamate, while curative therapy of CPS1D requires liver transplantation.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!