Research ArticleLactic acidosis

Phenylbutyrate Therapy for Pyruvate Dehydrogenase Complex Deficiency and Lactic Acidosis

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Science Translational Medicine  06 Mar 2013:
Vol. 5, Issue 175, pp. 175ra31
DOI: 10.1126/scitranslmed.3004986

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Lactic Acidosis: Fishing for a Drug

Doctors learn early in their training that lactic acidosis in a patient is a sign of trouble. Lactic acid is a byproduct of anaerobic metabolism and usually signifies that at least some part of a patient’s body is not receiving enough oxygen. A less common cause of lactic acidosis is an inborn error of metabolism, such as a deficiency of the pyruvate dehydrogenase complex (PDHC). Now, Ferriero and colleagues show that lactic acidosis can be treated by repurposing an existing drug called phenylbutyrate, which is already used for many metabolic disorders.

In vitro, the authors found that phenylbutyrate inhibited phosphorylation of the active subunit of PDHC; this protected the complex from inactivation and increased its enzyme activity in both wild-type fibroblasts and those isolated from patients with PDHC deficiency. The drug had similar effects on PDHC activity and decreased lactate concentrations in mice, including those that had undergone partial hepatectomy, an established model of lactic acidosis. In addition, in PDHC-deficient zebrafish, which suffer from symptoms such as feeding problems, lethargy, and darker coloration thought to result from poor light detection, phenylbutyrate treatment restored locomotion and pigmentation to near-normal levels.

The results obtained by Ferriero and coauthors will need to be confirmed in clinical trials. But because phenylbutyrate is already used in human patients and known to be safe, we may soon see a new treatment option for patients with PDHC deficiency and other diseases that cause lactic acidosis.

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