Polymerase γ gene POLG determines the risk of sodium valproate-induced liver toxicity.

Abstract

UNLABELLED:

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 γ (polγ), 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 VPA-induced liver toxicity (odds ratio = 23.6, 95% confidence interval [CI] = 8.4-65.8, P = 5.1 × 10⁻⁷). This was principally due to the p.Q1236H substitution which compromised polγ 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.

• Authors: Joanna D Stewart, Rita Horvath, Enrico Baruffini, Iliana Ferrero, Stefanie Bulst, Paul B Watkins, Robert J Fontana, Christopher P Day, Patrick F Chinnery
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 52 Issue 5 Pg. 1791-6 (Nov 2010) ISSN: 1527-3350 [Electronic] United States
• PMID: 21038416 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• GABA Agents
• Valproic Acid
• DNA Polymerase gamma
• DNA-Directed DNA Polymerase
• POLG protein, human

Topics

• Adolescent
• Adult
• Amino Acid Substitution
• Bipolar Disorder (drug therapy)
• Child
• Child, Preschool
• DNA Polymerase gamma
• DNA-Directed DNA Polymerase (genetics)
• Diffuse Cerebral Sclerosis of Schilder (genetics)
• GABA Agents (adverse effects, therapeutic use)
• Genetic Variation
• Headache (drug therapy)
• Hepatocytes (cytology, drug effects)
• Humans
• Liver (drug effects, pathology)
• Middle Aged
• Polymorphism, Single Nucleotide
• Risk Assessment
• Seizures (drug therapy)
• Valproic Acid (adverse effects, therapeutic use)
• Young Adult