title: Tamoxifen, an anticancer drug, is an activator of human aldehyde dehydrogenase 1A1.
abstract: The modulation of aldehyde dehydrogenase (ALDH) activity has been suggested as a promising option for the prevention or treatment of many diseases. To date, only few activating compounds of ALDHs have been described. In this regard, N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide has been used to protect the heart against ischemia/reperfusion damage. In the search for new modulating ALDH molecules, the binding capability of different compounds to the active site of human aldehyde dehydrogenase class 1A1 (ALDH1A1) was analyzed by molecular docking, and their ability to modulate the activity of the enzyme was tested. Surprisingly, tamoxifen, an estrogen receptor antagonist used for breast cancer treatment, increased the activity and decreased the Km for NAD(+) by about twofold in ALDH1A1. No drug effect on human ALDH2 or ALDH3A1 was attained, showing that tamoxifen was specific for ALDH1A1. Protection against thermal denaturation and competition with daidzin suggested that tamoxifen binds to the aldehyde site of ALDH1A1, resembling the interaction of N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide with ALDH2. Further kinetic analysis indicated that tamoxifen activation may be related to an increase in the Kd for NADH, favoring a more rapid release of the coenzyme, which is the rate-limiting step of the reaction for this isozyme. Therefore, tamoxifen might improve the antioxidant response, which is compromised in some diseases.
authors.affiliation: Departamento de Bioquímica, Instituto Nacional de Cardiología, México D.F, México.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Belmont-Díaz
authors.forename: Luis F
authors.initials: LF
authors.lastname: Calleja-Castañeda
authors.forename: Belem
authors.initials: B
authors.lastname: Yoval-Sánchez
authors.forename: José S
authors.initials: JS
authors.lastname: Rodríguez-Zavala
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D009243:NAD / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D050697:Retinal Dehydrogenase; D013629:Tamoxifen / Q000737:chemistry / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D020536:Enzyme Activators; D011994:Recombinant Proteins; D013629:Tamoxifen; D009243:NAD; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase
keywords: ALDH1A1; aldehyde dehydrogenases; lipid peroxidation products; oxidative stress; tamoxifen