title: Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 East Montview Blvd., Aurora, CO 80045, USA.
authors.forename: Vindhya
authors.initials: V
authors.lastname: Koppaka
authors.forename: David C
authors.initials: DC
authors.lastname: Thompson
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Manuel
authors.initials: M
authors.lastname: Ellermann
authors.forename: Kyriacos C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: Risto O
authors.initials: RO
authors.lastname: Juvonen
authors.forename: Dennis
authors.initials: D
authors.lastname: Petersen
authors.forename: Richard A
authors.initials: RA
authors.lastname: Deitrich
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Hurley
authors.forename: Vasilis
authors.initials: V
authors.lastname: Vasiliou
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D000444:Aldehyde Dehydrogenase