Polymerase gamma Gene POLG Determines the Risk of Sodium Valproate-Induced Liver Toxicity

Abstract

Sodium valproate (VPA) is widely used throughout the world to treat epilepsy, migraine,
chronic headache, bipolar disorder, and as adjuvant chemotherapy. VPA toxicity is an
uncommon but potentially fatal cause of idiosyncratic liver injury. Rare mutations in
POLG, which codes for the mitochondrial DNA polymerase c (polc), cause Alpers-Huttenlocher
syndrome (AHS). AHS is a neurometabolic disorder associated with an increased
risk of developing fatal VPA hepatotoxicity. We therefore set out to determine whether
common genetic variants in POLG explain why some otherwise healthy individuals develop
VPA hepatotoxicity. We carried out a prospective study of subjects enrolled in the
Drug Induced Liver Injury Network (DILIN) from 2004 to 2008 through five US centers.
POLG was sequenced and the functional consequences of VPA and novel POLG variants
were evaluated in primary human cell lines and the yeast model system Saccharomyces cerevisiae.
Heterozygous genetic variation in POLG was strongly associated with VPAinduced
liver toxicity (odds ratio 5 23.6, 95% confidence interval [CI] 5 8.4-65.8, P 5
5.1 3 1027). This was principally due to the p.Q1236H substitution which compromised
polc function in yeast. Therapeutic doses of VPA inhibited human cellular proliferation
and high doses caused nonapoptotic cell death, which was not mediated through
mitochondrial DNA depletion, mutation, or a defect of fatty acid metabolism.
Conclusion: These findings implicate impaired liver regeneration in VPA toxicity and show
that prospective genetic testing of POLG will identify individuals at high risk of this
potentially fatal consequence of treatment. (HEPATOLOGY 2010;52:1791-1796)

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ORCID for Joanna D Stewart: orcid.org/0000-0002-2608-1967

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