Aldehyde dehydrogenase inhibitors: A comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application

Vindhya Koppaka, David C. Thompson, Ying Chen, Manuel Ellermann, Kyriacos C. Nicolaou, Risto O. Juvonen, Dennis Petersen, Richard A. Deitrich, Thomas Hurley, Vasilis Vasiliou Dr.

Research output: Contribution to journalArticle

201 Citations (Scopus)

Abstract

Aldehyde dehydrogenases (ALDHs) belong to a superfamily of enzymes that play a key role in the metabolism of aldehydes of both endogenous and exogenous derivation. The human ALDH superfamily comprises 19 isozymes that possess important physiological and toxicological functions. The ALDH1A subfamily plays a pivotal role in embryogenesis and development by mediating retinoic acid signaling. ALDH2, as a key enzyme that oxidizes acetaldehyde, is crucial for alcohol metabolism. ALDH1A1 and ALDH3A1 are lens and corneal crystallins, which are essential elements of the cellular defense mechanism against ultraviolet radiation-induced damage in ocular tissues. Many ALDH isozymes are important in oxidizing reactive aldehydes derived from lipid peroxidation and thereby help maintain cellular homeostasis. Increased expression and activity of ALDH isozymes have been reported in various human cancers and are associated with cancer relapse. As a direct consequence of their significant physiological and toxicological roles, inhibitors of the ALDH enzymes have been developed to treat human diseases. This review summarizes known ALDH inhibitors, their mechanisms of action, isozyme selectivity, potency, and clinical uses. The purpose of this review is to 1) establish the current status of pharmacological inhibition of the ALDHs, 2) provide a rationale for the continued development of ALDH isozyme-selective inhibitors, and 3) identify the challenges and potential therapeutic rewards associated with the creation of such agents.

Original languageEnglish
Pages (from-to)520-539
Number of pages20
JournalPharmacological Reviews
Volume64
Issue number3
DOIs
StatePublished - 2012

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Aldehyde Dehydrogenase
Substrate Specificity
Pharmacology
Isoenzymes
Aldehydes
Toxicology
Enzymes
Crystallins
Acetaldehyde
Defense Mechanisms
Tretinoin
Reward
Lipid Peroxidation
Lenses
Embryonic Development
Neoplasms
Homeostasis
Alcohols
Radiation
Recurrence

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Aldehyde dehydrogenase inhibitors : A comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. / Koppaka, Vindhya; Thompson, David C.; Chen, Ying; Ellermann, Manuel; Nicolaou, Kyriacos C.; Juvonen, Risto O.; Petersen, Dennis; Deitrich, Richard A.; Hurley, Thomas; Vasiliou Dr., Vasilis.

In: Pharmacological Reviews, Vol. 64, No. 3, 2012, p. 520-539.

Research output: Contribution to journalArticle

Koppaka, V, Thompson, DC, Chen, Y, Ellermann, M, Nicolaou, KC, Juvonen, RO, Petersen, D, Deitrich, RA, Hurley, T & Vasiliou Dr., V 2012, 'Aldehyde dehydrogenase inhibitors: A comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application', Pharmacological Reviews, vol. 64, no. 3, pp. 520-539. https://doi.org/10.1124/pr.111.005538
Koppaka, Vindhya ; Thompson, David C. ; Chen, Ying ; Ellermann, Manuel ; Nicolaou, Kyriacos C. ; Juvonen, Risto O. ; Petersen, Dennis ; Deitrich, Richard A. ; Hurley, Thomas ; Vasiliou Dr., Vasilis. / Aldehyde dehydrogenase inhibitors : A comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. In: Pharmacological Reviews. 2012 ; Vol. 64, No. 3. pp. 520-539.
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