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.