Toxicity of Valproic Acid in Mice with Decreased Plasma and Tissue Carnitine Stores

Abstract

The aim of this study was to investigate whether a decrease in carnitine body stores is a risk factor for valproic acid (VPA)-associated hepatotoxicity and to explore the effects of VPA on carnitine homeostasis in mice with decreased carnitine body stores. Therefore, heterozygous juvenile visceral steatosis (jvs) ϩ/Ϫ mice, an animal model with decreased carnitine stores caused by impaired renal reabsorption of carnitine, and the corresponding wild-type mice were treated with subtoxic oral doses of VPA (0.1 g/g b.wt./day) for 2 weeks. In jvs ϩ/Ϫ mice, but not in wild-type mice, treatment with VPA was associated with the increased plasma activity of aspartate aminotransferase and alkaline phosphatase. Furthermore, jvs ϩ/Ϫ mice revealed reduced palmitate metabolism assessed in vivo and microvesicular steatosis of the liver. The creatine kinase activity was not affected by treatment with VPA. In liver mitochondria isolated from mice that were treated with VPA, oxidative metabolism of L-glutamate, succinate, and palmitate, as well as ␤-oxidation of palmitate, were decreased compared to vehicle-treated wild-type mice or jvs ϩ/Ϫ mice. In comparison to vehicle-treated wild-type mice, vehicle-treated jvs ϩ/Ϫ mice had decreased carnitine plasma and tissue levels. Treatment with VPA was associated with an additional decrease in carnitine plasma (wildtype mice and jvs ϩ/Ϫ mice) and tissue levels (jvs ϩ/Ϫ mice) and a shift of the carnitine pools toward short-chain acylcarnitines. We conclude that jvs ϩ/Ϫ mice reveal a more accentuated hepatic toxicity by VPA than the corresponding wildtype mice. Therefore, decreased carnitine body stores can be regarded as a risk factor for hepatotoxicity associated with VPA.

Hepatotoxicity of New Oral Anticoagulants (NOACs)

“…As an example, impaired function of the mitochondrial respiratory chain [18] and impaired function of DNA polymerase c [19] have been reported to be susceptibility factors for valproate-associated liver failure. In experimental animals, impaired mitochondrial b-oxidation has been reported to be a risk factor for valproate [20] or for dronedarone-associated [21] liver injury. Another example is liver inflammation, which has been reported to be a susceptibility factor for liver injury associated with fluoroquinolones in experimental animals [22].…”

New insights on the mechanisms of valproate-induced hyperammonemia: Inhibition of hepatic N-acetylglutamate synthase activity by valproyl-CoA

“…(2) an indirect effect on CPS I, namely by an interference of the drug with the synthesis of NAG, the essential activator of this enzyme [12,[24][25][26][27]; (3) a VPA-induced inhibition of mitochondrial FAO, through several synergistic mechanisms: VPA or metabolites may induce secondary carnitine depletion and ultimately reduce the bioavailability of acetyl-CoA [10,20,28,29]. This latter metabolite is essential for energy production and is one of the substrates for NAGS activity [11,20,30].…”

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

“…Preexisting mitochondrial impairment or deficiency of cofactors involved with valproate metabolism (e.g. carnitine) may represent risk factors for hepatotoxicity [82] .…”