Alkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of active enzyme homogentisate 1,2-dioxygenase (HGD). The primary consequence of HGD deficiency is increased circulating homogentisic acid (HGA), the main agent in the pathology of AKU disease. Here we report the first metabolomic analysis of AKU homozygous knockout ( ) mice to model the wider metabolic effects of deletion and the implication for AKU in humans. Untargeted metabolic profiling was performed on urine from AKU ( = 15) and non-AKU control ( = 14) mice by liquid chromatography high-resolution time-of-flight mass spectrometry (Experiment 1). The metabolites showing alteration in were further investigated in AKU mice ( = 18) and patients from the UK National AKU Centre ( = 25) at baseline and after treatment with the HGA-lowering agent nitisinone (Experiment 2). A metabolic flux experiment was carried out after administration of C-labelled HGA to ( = 4) and ( = 4) mice (Experiment 3) to confirm direct association with HGA. mice showed the expected increase in HGA, together with unexpected alterations in tyrosine, purine and TCA-cycle pathways. Metabolites with the greatest abundance increases in were HGA and previously unreported sulfate and glucuronide HGA conjugates, these were decreased in mice and patients on nitisinone and shown to be products from HGA by the C-labelled HGA tracer. Our findings reveal that increased HGA in AKU undergoes further metabolism by mainly phase II biotransformations. The data advance our understanding of overall tyrosine metabolism, demonstrating how specific metabolic conditions can elucidate hitherto undiscovered pathways in biochemistry and metabolism.
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http://dx.doi.org/10.1016/j.gendis.2021.02.007 | DOI Listing |
Cancer Chemother Pharmacol
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Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt.
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December 2024
Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
Parkinson's disease (PD) is a multifactorial disease caused by irreversible progressive loss of dopaminergic neurons (DANs). Recent studies have reported the successful conversion of astrocytes into DANs by repressing polypyrimidine tract binding protein 1 (PTBP1), which led to the rescue of motor symptoms in a chemically-induced mouse model of PD. However, follow-up studies have questioned the validity of this astrocyte-to-DAN conversion model.
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December 2024
Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China.
Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor, and the development of accurate predictive models for prognosis and drug sensitivity remains challenging.
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Clin Pharmacol Drug Dev
December 2024
Gossamer Bio, Inc., San Diego, CA, USA.
Seralutinib, an inhaled, small-molecule tyrosine kinase inhibitor in clinical development for the treatment of pulmonary arterial hypertension (PAH), was evaluated for its potential as a perpetrator or victim of a metabolic and transporter-based drug-drug interactions in 2 phase 1 studies. In study 1, 24 participants received a cocktail of probe substrates: caffeine (CYP1A2), montelukast (CYP2C8), flurbiprofen (CYP2C9), midazolam (CYP3A), and pravastatin (OATP1B1/1B3), plus digoxin (P-gp) with or without seralutinib. In study 2, 19 participants received seralutinib with/without itraconazole, a strong CYP3A inhibitor, or fosaprepitant, a weak CYP3A inhibitor.
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December 2024
Clinical and Translational Research Center, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China. Electronic address:
Aims: Preeclampsia (PE) is an unusual multisystem condition that occurs during pregnancy and is characterized by maternal endothelial dysfunction and damage to various organs. The catabolism of L-tryptophan (Trp) is involved in various biological activities, including healthy pregnancy. Our previous work revealed that PE significantly elevated the concentration of indole-3-lactic acid (ILA), a Trp derivative, during the third trimester of pregnancy.
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