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

Polymerase gamma Gene POLG Determines the Risk of Sodium Valproate-Induced Liver Toxicity
Polymerase gamma Gene POLG Determines the Risk of Sodium Valproate-Induced Liver Toxicity
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)
0270-9139
1791-1796
Stewart, Joanna D
e1ec9784-39cc-48ed-9f4f-2a05d25f2106
Horvath, Rita
e41c9ffa-b0a0-4ebb-a44a-b98a2c6c23cd
Baruffini, Enrico
86cec356-1223-48e3-9543-89ece11fddb6
Ferrero, Iliana
39cc50d6-f2ae-4faa-a2b5-21da164fe6e1
Bulst, Stefanie
33f45952-4959-48bc-9986-227087693bd2
Watkins, Paul B.
9a8923fa-ef16-4405-b794-1b5f1d229ce6
Fontana, Robert J.
27d06952-77be-4ab2-87ab-c31cae4d7e37
Day, Christopher P.
4f414f3d-0f22-4384-974b-9368fb93dc0a
Chinnery, Patrick F.
a39c5ef7-0cac-401c-a3fb-2e0e2626e6dc
Stewart, Joanna D
e1ec9784-39cc-48ed-9f4f-2a05d25f2106
Horvath, Rita
e41c9ffa-b0a0-4ebb-a44a-b98a2c6c23cd
Baruffini, Enrico
86cec356-1223-48e3-9543-89ece11fddb6
Ferrero, Iliana
39cc50d6-f2ae-4faa-a2b5-21da164fe6e1
Bulst, Stefanie
33f45952-4959-48bc-9986-227087693bd2
Watkins, Paul B.
9a8923fa-ef16-4405-b794-1b5f1d229ce6
Fontana, Robert J.
27d06952-77be-4ab2-87ab-c31cae4d7e37
Day, Christopher P.
4f414f3d-0f22-4384-974b-9368fb93dc0a
Chinnery, Patrick F.
a39c5ef7-0cac-401c-a3fb-2e0e2626e6dc

Stewart, Joanna D, Horvath, Rita, Baruffini, Enrico, Ferrero, Iliana, Bulst, Stefanie, Watkins, Paul B., Fontana, Robert J., Day, Christopher P. and Chinnery, Patrick F. (2010) Polymerase gamma Gene POLG Determines the Risk of Sodium Valproate-Induced Liver Toxicity. Hepatology, 52 (5), 1791-1796. (doi:10.1002/hep.23891). (PMID:21038416)

Record type: Article

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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Published date: 2010
Organisations: Centre for Biological Sciences

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Local EPrints ID: 355893
URI: http://eprints.soton.ac.uk/id/eprint/355893
ISSN: 0270-9139
PURE UUID: e7d8f71b-6823-4a1c-8fcb-53007d129925
ORCID for Joanna D Stewart: ORCID iD orcid.org/0000-0002-2608-1967

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Date deposited: 04 Sep 2013 17:14
Last modified: 18 Feb 2021 17:20

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Contributors

Author: Joanna D Stewart ORCID iD
Author: Rita Horvath
Author: Enrico Baruffini
Author: Iliana Ferrero
Author: Stefanie Bulst
Author: Paul B. Watkins
Author: Robert J. Fontana
Author: Christopher P. Day
Author: Patrick F. Chinnery

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