Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review

Silva, Margarida F. B.; Aires, C. C. P.; Luis, Paula B.; Ruiter, J. P. N.; IJlst, Lodewijk; Durán, Marinus; Wanders, Ronald J. A.; Almeida, Isabel Tavares de

doi:10.1007/s10545-008-0841-x

Cited by 336 publications

(293 citation statements)

References 102 publications

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“…10). Trapping of CoA by the metabolism of some drugs has been implicated in the deleterious effects of the drugs (44). Also, in some inborn errors of metabolism, the accumulation of CoA esters has been implicated in the physiopathology of the diseases (41).…”

Section: -Phosphoacyl-coas In 4-hydroxyacid Metabolismmentioning

confidence: 99%

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Zhang

Kombu

Kasumov

et al. 2009

Journal of Biological Chemistry

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4-Hydroxyacids are products of ubiquitously occurring lipid peroxidation (C 9 , C 6 ) or drugs of abuse (C 4 , C 5 ). We investigated the catabolism of these compounds using a combination of metabolomics and mass isotopomer analysis. Livers were perfused with various concentrations of unlabeled and labeled saturated 4-hydroxyacids (C 4 to C 11 ) or 4-hydroxynonenal. All the compounds tested form a new class of acyl-CoA esters, 4-hydroxy-4-phosphoacyl-CoAs, characterized by liquid chromatography-tandem mass spectrometry, accurate mass spectrometry, and 31 P-NMR. All 4-hydroxyacids with five or more carbons are metabolized by two new pathways. The first and major pathway, which involves 4-hydroxy-4-phosphoacylCoAs, leads in six steps to the isomerization of 4-hydroxyacylCoA to 3-hydroxyacyl-CoAs. The latter are intermediates of physiological ␤-oxidation. The second and minor pathway involves a sequence of ␤-oxidation, ␣-oxidation, and ␤-oxidation steps. In mice deficient in succinic semialdehyde dehydrogenase, high plasma concentrations of 4-hydroxybutyrate result in high concentrations of 4-hydroxy-4-phospho-butyryl-CoA in brain and liver. The high concentration of 4-hydroxy-4-phospho-butyryl-CoA may be related to the cerebral dysfunction of subjects ingesting 4-hydroxybutyrate and to the mental retardation of patients with 4-hydroxybutyric aciduria. Our data illustrate the potential of the combination of metabolomics and mass isotopomer analysis for pathway discovery.4-Hydroxy-n-acids are involved in different areas of mammalian metabolism. Some unsaturated 4-hydroxyacids are derived from 4-hydroxynonenal and 4-hydroxyhexenal, which are products of lipid peroxidation (1). The metabolism of 4-hydroxynonenal has been extensively studied, especially its conjugation with glutathione (2), covalent modification of proteins (3, 4), and conversion to 4-hydroxynonenoate, 4-hydroxynonanoate and 1,4-dihydroxynonene, as well as its role in inflammatory processes (1, 5-11). However, the catabolism of its carbon skeleton has not been unraveled. The four-carbon 4-hydroxybutyrate is a physiological neurotransmitter derived from ␥-aminobutyrate. Humans with inborn disorder of succinic semialdehyde dehydrogenase have high 4-hydroxybutyrate concentrations in body fluids, mental retardation, and seizures (12). 4-Hydroxybutyrate is also a drug of abuse that impairs the capacity to exercise judgment for unknown reasons. 4-Hydroxybutyrate is used for the treatment of narcolepsy (13). Its known metabolism (14, 15) proceeds via oxidation to succinic semialdehyde and then to succinate, an intermediate of the citric acid cycle. The five-carbon 4-hydroxypentanoate is also a drug of abuse (16). The calcium salt of a compound closely related to 4-hydroxypentanoate, levulinate (4-ketopentanoate, 4-ketovalerate), is used as an oral or intravenous source of calcium in humans.We conducted a study on the catabolism of C 4 to C 11 4-hydroxyacids in perfused rat livers using a combination of metabolomics (17,18) and mass isotopomer analysis 2 (19)....

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Section: -Phosphoacyl-coas In 4-hydroxyacid Metabolismmentioning

confidence: 99%

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Zhang

Kombu

Kasumov

et al. 2009

Journal of Biological Chemistry

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“…Valproate metabolization occurs primarily in the liver mitochondria, and thus should be avoided in cases of mitochondrial disorders, as it may stress vital pathways that intensify the genetic damage [10].…”

Section: Discussionmentioning

confidence: 99%

Hyperprolinemia as a clue in the diagnosis of a patient with psychiatric manifestations

Duarte

Afonso

Moreira

et al. 2017

Brain and Development

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Lately, microdeletions of the 22q region, responsible for DiGeorge syndrome or velocardiofacial syndrome, have been increasingly related to neuropsychiatric disorders including schizophrenia and bipolar disorder. These manifestations seem to be related to certain genes located in the hemideleted region such as the proline dehydrogenase (PRODH) and the catechol-o-methyltransferase (COMT) genes.We describe a teenager who started his adolescent psychiatric care presenting cognitive impairment, irritable mood and aggressive behaviour with schizophrenia-like symptoms that scored 153 in the Positive and Negative Symptoms Scale (PANSS) assessment.Worsening of symptoms when the patient was treated with valproic acid, and plasma aminoacids showing an increase in alanine and proline, suggested a mitochondrial involvement of the proline metabolic pathway. Mild dysmorphic features also suggested a possible 22q11 deletion syndrome that was confirmed. A mutation for Hyperprolinemia type I was also detected.Knowledge of the correct diagnosis was crucial for an adequate treatment.

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“…The mechanism of valproate toxicity is purported to be via interference with mitochondrial beta oxidation. [12] Neurotoxicity in GA1 is also mediated through mitochondrial injury. Three of our patients had a movement disorder.…”

Section: Discussionmentioning

confidence: 99%

A review of patients with glutaric aciduria type 1 at Inkosi Albert Luthuli Central Hospital, Durban, South Africa

2017

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Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review

Cited by 336 publications

References 102 publications

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Hyperprolinemia as a clue in the diagnosis of a patient with psychiatric manifestations

A review of patients with glutaric aciduria type 1 at Inkosi Albert Luthuli Central Hospital, Durban, South Africa

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