Glutathione depletion by valproic acid in sandwich-cultured rat hepatocytes: Role of biotransformation and temporal relationship with onset of toxicity

Kiang, Tony K. L.; Teng, Xiao Wei; Surendradoss, Jayakumar; Karagiozov, Stoyan; Abbott, Frank S.; Chang, Thomas K. H.

doi:10.1016/j.taap.2011.03.004

Cited by 54 publications

(33 citation statements)

References 30 publications

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“…dmd.aspetjournals.org of VPA toxicity. The lack of an effect of b-naphthoflavone on VPA toxicity cannot be due to the increased cellular GSH content by b-naphthoflavone because depletion of GSH has been reported as a consequence rather than a cause of VPA toxicity in cultured rat hepatocytes (Kiang et al, 2011). In support of our finding that in situ generated VPA-G is nontoxic to rat hepatocytes, previous studies have shown that VPA-G is one of the least reactive and the most stable acyl glucuronides (Stachulski et al, 2006).…”

Section: Discussionsupporting

confidence: 81%

Evaluation of In Situ Generated Valproyl 1-O-β-Acyl Glucuronide in Valproic Acid Toxicity in Sandwich-Cultured Rat Hepatocytes

2014

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Acyl glucuronides are reactive electrophilic metabolites implicated in the toxicity of carboxylic acid drugs. Valproyl 1-O-b-acyl glucuronide (VPA-G), which is a major metabolite of valproic acid (VPA), has been linked to the development of oxidative stress in VPA-treated rats. However, relatively little is known about the toxicity of in situ generated VPA-G and its contribution to VPA hepatotoxicity. Therefore, we investigated the effects of modulating the in situ formation of VPA-G on lactate dehydrogenase (LDH) release (a marker of necrosis), BODIPY 558/568 C 12 accumulation (a marker of steatosis), and cellular glutathione (GSH) content in VPA-treated sandwich-cultured rat hepatocytes. VPA increased LDH release and BODIPY 558/568 C 12 accumulation, whereas it had little or no effect on total GSH content. Among the various uridine 59-diphospho-glucuronosyltransferase inducers evaluated, b-naphthoflavone produced the greatest increase in VPA-G formation. This was accompanied by an attenuation of the increase in BODIPY 558/568 C 12 accumulation, but did not affect the change in LDH release or total GSH content in VPA-treated hepatocytes. Inhibition of in situ formation of VPA-G by borneol was not accompanied by substantive changes in the effects of VPA on any of the toxicity markers. In a comparative study, in situ generated diclofenac glucuronide was not toxic to rat hepatocytes, as assessed using the same chemical modulators, thereby demonstrating the utility of the sandwich-cultured rat hepatocyte model. Overall, in situ generated VPA-G was not toxic to sandwich-cultured rat hepatocytes, suggesting that VPA glucuronidation per se is not expected to be a contributing mechanism for VPA hepatotoxicity.

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Section: Discussionsupporting

confidence: 81%

Evaluation of In Situ Generated Valproyl 1-O-β-Acyl Glucuronide in Valproic Acid Toxicity in Sandwich-Cultured Rat Hepatocytes

2014

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“…Thus, when cultured under appropriate conditions, SCRH do not exhibit biliary stasis, intracellular bile acids are within the range of previously reported values (Marion et al, 2012), and SCRH exhibit toxicity when BSEP is inhibited (Kemp and Brouwer, 2004;Marion et al, 2007;Ogimura et al, 2011). The content of reduced glutathione in SCRH is normal and is decreased markedly by exposure to toxicants that deplete glutathione in vivo (Kiang et al, 2011). Therefore, we selected the SCRH model for the present studies.…”

Section: Discussionsupporting

confidence: 59%

Combination Lopinavir and Ritonavir Alter Exogenous and Endogenous Bile Acid Disposition in Sandwich-Cultured Rat Hepatocytes

et al. 2012

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Inhibition of the bile salt export pump (BSEP) can cause intracellular accumulation of bile acids and is a risk factor for drug-induced liver injury in humans. Antiretroviral protease inhibitors lopinavir (LPV) and ritonavir (RTV) are reported BSEP inhibitors. However, the consequences of LPV and RTV, alone and combined (LPV/r), on hepatocyte viability, bile acid transport, and endogenous bile acid disposition in rat hepatocytes have not been examined.

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“…The cytochromes P450 have been shown to form the 4-ene-VPA and 3-OH-VPA metabolites, whereas 2-ene-VPA ad 3-OH-VPA metabolites result from b-oxidation. 3-Keto-VPA is formed by dehydrogenation of the cytochrome P450 formation of 3-OH-VPA (Kiang et al, 2011). Primary mouse hepatocytes were incubated with 20 mM of 2-ene-VPA, 4-ene-VPA, and 3-OH-VPA and compared with a vehicletreated control (Fig.…”

Section: Vpa Stimulates Phosphorylation Of Ampk and Acc In Hepatocytesmentioning

confidence: 99%

Valproic Acid Is a Novel Activator of AMP-Activated Protein Kinase and Decreases Liver Mass, Hepatic Fat Accumulation, and Serum Glucose in Obese Mice

Avery

Bumpus

2013

Mol Pharmacol

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Valproic acid (VPA) is a widely prescribed anticonvulsant for the treatment of epilepsy. Here we demonstrate that VPA is a novel activator of AMP-activated protein kinase (AMPK), a key regulator of cellular metabolism, using primary mouse and human hepatocytes. Incubation of primary mouse hepatocytes with VPA resulted in increased levels of phosphorylated AMPK and acetylCoA carboxylase (ACC). This finding was recapitulated using primary human hepatocytes. Pretreatment of mouse hepatocytes with a small-molecule inhibitor of AMPK, Compound C (6-[4-(2-piperidin-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine), abrogated the phosphorylation of ACC following treatment with VPA. The cytochrome P450 inhibitor 1-aminobenzotriazole blocked the VPA-stimulated phosphorylation of AMPK, suggesting a requirement for biotransformation of VPA. In line with this, treatment of hepatocytes with metabolites of VPA resulted in increased phosphorylation of AMPK/ACC as compared with VPA. Treatment of ob/ob mice with VPA for 14 days resulted in decreased liver masses, hepatic fat accumulation, and serum glucose. These results paralleled those observed in mice treated with metformin. In addition, a targeted mass spectrometry-based metabolomics assay revealed several small molecules that were differentially abundant in the serum of ob/ob mice treated with VPA as compared with vehicle-treated mice. These studies are the first to establish VPA and its metabolites as in vitro activators of AMPK.

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Glutathione depletion by valproic acid in sandwich-cultured rat hepatocytes: Role of biotransformation and temporal relationship with onset of toxicity

Cited by 54 publications

References 30 publications

Evaluation of In Situ Generated Valproyl 1-O-β-Acyl Glucuronide in Valproic Acid Toxicity in Sandwich-Cultured Rat Hepatocytes

Evaluation of In Situ Generated Valproyl 1-O-β-Acyl Glucuronide in Valproic Acid Toxicity in Sandwich-Cultured Rat Hepatocytes

Combination Lopinavir and Ritonavir Alter Exogenous and Endogenous Bile Acid Disposition in Sandwich-Cultured Rat Hepatocytes

Valproic Acid Is a Novel Activator of AMP-Activated Protein Kinase and Decreases Liver Mass, Hepatic Fat Accumulation, and Serum Glucose in Obese Mice

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