An update on the use of benzoate, phenylacetate and phenylbutyrate ammonia scavengers for interrogating and modifying liver nitrogen metabolism and its implications in urea cycle disorders and liver disease

ABSTRACT

Introduction: Ammonia-scavenging drugs, benzoate and phenylacetate (PA)/phenylbutyrate (PB), modulate hepatic nitrogen metabolism mainly by providing alternative pathways for nitrogen disposal.

Areas covered: We review the major findings and potential novel applications of ammonia-scavenging drugs, focusing on urea cycle disorders and liver disease.

Expert opinion: For over 40 years, ammonia-scavenging drugs have been used in the treatment of urea cycle disorders. Recently, the use of these compounds has been advocated in acute liver failure and cirrhosis for reducing hyperammonemic-induced hepatic encephalopathy. The efficacy and mechanisms underlying the antitumor effects of these ammonia-scavenging drugs in liver cancer are more controversial and are discussed in the review. Overall, as ammonia-scavenging drugs are usually safe and well tolerated among cancer patients, further studies should be instigated to explore the role of these drugs in liver cancer. Considering the relevance of glutamine metabolism to the progression and resolution of liver disease, we propose that ammonia-scavenging drugs might also be used to non-invasively probe liver glutamine metabolism in vivo. Finally, novel derivatives of classical ammonia-scavenging drugs with fewer and less severe adverse effects are currently being developed and used in clinical trials for the treatment of acute liver failure and cirrhosis.

KEYWORDS:

• Glutamine
• urea cycle disorders
• acute liver failure
• cirrhosis
• hepatocellular carcinoma
• phenylacetate
• phenylbutyrate
• benzoate

Article highlights

• Ammonia-scavenging drugs target liver nitrogen metabolism in urea cycle disorders by offering an alternative pathway for nitrogen disposal through the urinary excretion of hippurate and phenylacetylglutamine.

• Treatment with ammonia-scavenging drugs has been shown to reduce hepatic encephalopathy events by lowering blood ammonia both in cirrhosis and in mouse models of acute liver failure.

• Phenylacetate and phenylbutyrate-based treatment provides a means for hepatic glutamine depletion in liver cancer highlighting its therapeutic potential to target glutamine-addicted cancer cells.

• Phenylacetate and phenylbutyrate-based therapy is able to selectively reduce branched-chain amino acids and is currently being used in clinical trials on patients with maple syrup urine disease, a classical inborn error of amino acid metabolism.

• Benzoate, phenylacetate and phenylbutyrate and their excretable urinary by-products, hippurate and phenylacetylglutamine can be used to non-invasively assess intermediary metabolism of carbohydrate in the liver and potentially in vivo liver glutamine metabolism.

• There is currently great interest in the development of more efficient ammonia-scavenging pharmacological derivatives with fewer side effects and greater therapeutic potential.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by grants from NIH (National Institute of Health) (US Department of Health and Human services)- CA172086, Ministerio de Economía y Competitividad: SAF2014-54658-R integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovación 2013-2016 cofinanciado con Fondos FEDER to M.L.M.-C, EITB BIO15/CA/014 (M.L.M-C.) y Asociación Española contra el Cáncer (M.L.M-C. and T.C.D.), Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III.