Acute Valproate Administration Impairs Methionine Metabolism in Rats

Úbeda, Natalia; Alonso-Aperte, Elena; Varela‐Moreiras, Gregorio

doi:10.1093/jn/132.9.2737

Cited by 42 publications

(25 citation statements)

References 44 publications

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“…Consistent with many previous results (Seçkin et al, 1999;Cotariu et al, 1990;Úbeda et al, 2002), hepatotoxicity was induced by high doses of VPA (100 and 500 mg kg ). Serum levels of a-glutathione-S-transferase, the sensitive biomarker for hepatocyte injury, increased by 6-and 8-fold in the treatment groups administered 100 and 500 mg kg -1 VPA, respectively, as compared with the control group (P < 0.0001, ANOVA with Dunnett's multiple comparison test).…”

Section: Resultssupporting

confidence: 92%

Dose‐dependent pharmacokinetics of toxic metabolites is not related to increased toxicity following high‐dose valproic acid in rats

Jung

Kim

Lee

et al. 2010

J of Applied Toxicology

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It has been reported that urinary excretion of two metabolites of valproic acid (VPA), 4-ene-valproic acid (4-VPA)and 2,4-diene-valproic acid (2,4-VPA), increased exponentially with the administration of high doses of VPA, and this increased formation of toxic metabolites could be related to VPA hepatotoxicity in humans. The aim of this study was to investigate whether the plasma level of 4-VPA and 2,4-VPA in rats corresponds to the urinary data for the same metabolites in humans.After the oral administration of VPA at doses of 20, 100 and 500 mg kg-1 in rats, the AUC0–24 h, 4-VPA/AUC0–24 h, VPA ratios (0.0399,0.0120 and 0.0100 for 20, 100 and 500 mg kg-1, respectively) and AUC0–24 h, 2,4-VPA/AUC0–24 h, VPA ratios (0.00104, 0.00201 and 0.00141, respectively) did not increase with increasing doses of VPA in rats. Thus, the plasma exposure of toxic metabolites normalized by dose remained unchanged (for 2,4-VPA) or even decreased (for 4-VPA) following high-dose VPA administration;this contradicts the findings of previous studies. Our results suggest that toxicity induced by high doses of VPA cannot be explained by a nonlinear increase of toxic metabolites in rats.

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Section: Resultssupporting

confidence: 92%

Dose‐dependent pharmacokinetics of toxic metabolites is not related to increased toxicity following high‐dose valproic acid in rats

Jung

Kim

Lee

et al. 2010

J of Applied Toxicology

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“…Solution of the rat BHMT crystal showed an α helix formed by residues 381-407 extending from one monomer to the opposite to bind the dimers, contributing additional interactions to tetramer stabilization [49]. Electron maps contributed new data such as the N-terminal (1-9) and the L2 (82)(83)(84)(85)(86)(87)(88)(89)(90) loop. This last loop shows high mobility and plays a role in Hcy binding.…”

Section: Bhmt Structurementioning

confidence: 99%

Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism?

Pajares

Pérez‐Sala

2006

Cell. Mol. Life Sci.

171

108

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Betaine homocysteine methyltransferase (BHMT), a Zn(2+)-dependent thiolmethyltransferase, contributes to the regulation of homocysteine levels, increases in which are considered a risk factor for cardiovascular diseases. Most plasma homocysteine is generated through the liver methionine cycle, in which BHMT metabolizes approximately 25% of this non-protein amino acid. This process allows recovery of one of the three methylation equivalents used in phosphatidylcholine synthesis through transmethylation, a major homocysteine-producing pathway. Although BHMT has been known for over 40 years, the difficulties encountered in its isolation precluded detailed studies until very recently. Thus, the last 10 years, since the sequence became available, have yielded extensive structural and functional data. Moreover, recent findings offer clues for potential new functions for BHMT. The purpose of this review is to provide an integrated view of the knowledge available on BHMT, and to analyze its putative roles in other processes through interactions uncover to date.

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“…Lower brain AdoHcy concentrations may stimulate epileptic behavior because this metabolite appears to be an endogenous neural inhibitor. Evidence supporting this theory includes the anticonvulsant effect of AdoHcy [6] and the fact many common antiepileptic drugs including valproate [29], phenobarbital [1], and diazepam [9] can elevate AdoHcy levels.…”

Section: Introductionmentioning

confidence: 99%

Improved rotorod performance and hyperactivity in mice deficient in a protein repair methyltransferase

Vitali¹,

Clarke²

2004

Behavioural Brain Research

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The protein l-isoaspartate (d-aspartate)-O-methyltransferase participates in the repair of age-induced protein damage by initiating the conversion of abnormal aspartyl residues within proteins to normal l-aspartyl residues. Previous studies have shown that mice deficient in the gene encoding this enzyme (Pcmt1−/−) accumulate damaged proteins, have altered levels of brain S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy), and suffer from epileptic seizures that result in death at an average age of about 42 days. In this study, we found that the behavior of Pcmt1−/− mice is abnormal in comparison to their wild-type (Pcmt1+/+) and heterozygous (Pcmt1+/−) littermates in two standard quantitative behavioral assays -the accelerating rotorod and the open-field test. On the accelerating rotorod, we found Pcmt1−/− mice actually perform significantly better than their heterozygous and wild-type littermates, a situation that has only been infrequently described in the literature and has not been described to date for epilepsy-prone mice. The Pcmt1−/− mice show, however, hyperactivity in the open-field test that becomes more pronounced with age, with a partial habituation with time in the chamber. Additionally, these mice demonstrate a strong thigmotaxic movement pattern. We present evidence that these phenotypes are not related to the alterations of the AdoMet/AdoHcy ratio in the brain and thus may be a function of the accumulation of damaged proteins. These results implicate a role for this enzyme in motor coordination and cerebellum development and suggest the importance of the function of the repair methyltransferase in hippocampal-dependent spatial learning.

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Acute Valproate Administration Impairs Methionine Metabolism in Rats

Cited by 42 publications

References 44 publications

Dose‐dependent pharmacokinetics of toxic metabolites is not related to increased toxicity following high‐dose valproic acid in rats

Dose‐dependent pharmacokinetics of toxic metabolites is not related to increased toxicity following high‐dose valproic acid in rats

Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism?

Improved rotorod performance and hyperactivity in mice deficient in a protein repair methyltransferase

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