Activation of ALDH1A1 by omeprazole reduces cell oxidative stress damage

Abstract

Under physiological conditions, cells produce low basal levels of reactive oxygen species (ROS); however, in pathologic conditions ROS production increases dramatically, generating high concentrations of toxic unsaturated aldehydes. Aldehyde dehydrogenases (ALDHs) are responsible for detoxification of these aldehydes protecting the cell. Due to the physiological relevance of these enzymes, it is important to design strategies to modulate their activity. It was previously reported that omeprazole activation of ALDH1A1 protected Escherichia coli cells overexpressing this enzyme, from oxidative stress generated by H 2 O 2 . In this work, omeprazole cell protection potential was evaluated in eukaryotic cells. AS-30D cell or hepatocyte suspensions were subjected to a treatment with omeprazole and exposure to light (that is required to activate omeprazole in the active site of ALDH) and then exposed to H 2 O 2 . Cells showed viability similar to control cells, total activity of ALDH was preserved, while cell levels of lipid aldehydes and oxidative stress markers were maintained low. Cell protection by omeprazole was avoided by inhibition of ALDHs with disulfiram, revealing the key role of these enzymes in the protection. Additionally, omeprazole also preserved ALDH2 (mitochondrial isoform) activity, diminishing lipid aldehyde levels and oxidative stress in this organelle, protecting mitochondrial respiration and transmembrane potential formation capacity, from the stress generated by H 2 O 2 . These results highlight the important role of ALDHs as part of the antioxidant system of the cell, since if the activity of these enzymes decreases under stress conditions, the viability of the cell is compromised.

Aldh1a1andScl25a30in diaphragmatic dysfunction

“…However, whether activation or inhibition of ALDH enzymes exerts beneficial effects depends on the specific conditions, necessitating a greater understanding of the role-played by ALDH1A1 in specific diseases. [43][44][45][46] Solute carrier family-25 (SLC25) is a superfamily of transporters in the mitochondrial inner membrane in mammals, and SLC25 member-30 (SLC25A30) has been implicated in the regulation of ROS. 47 The Slc25a30 gene encodes kidney mitochondrial carrier protein-1 (KMCP1), which transports sulfate and thiosulfate across the inner mitochondrial membrane and thereby modulates the level of the important gaseous signaling molecule, hydrogen sulfide (H 2 S).…”

“…However, whether activation or inhibition of ALDH enzymes exerts beneficial effects depends on the specific conditions, necessitating a greater understanding of the role-played by ALDH1A1 in specific diseases. 43–46…”

Genomic expansion of Aldh1a1 protects beavers against high metabolic aldehydes from lipid oxidation

“…A recent study showed that both alcohol and endogenous aldehydes damage chromosomes and increase the mutation rate of stem cells ( Garaycoechea et al, 2018 ). The activation of Aldh1a1 was found with the ability to reduce cell oxidative stress damage ( Calleja et al, 2021 ). We found that beaver cells exhibited better tolerance to ethanol than mouse cells and showed strikingly enhanced capabilities for metabolizing MDA and HNE ( Figure 2 ).…”

ALDH1A1 in Cancers: Bidirectional Function, Drug Resistance, and Regulatory Mechanism

“…In the past decade, researchers have found that ALDH1A1 had vital physiological and pathophysiological functions in many systems, such as the central nervous system, as well as inflammatory and metabolic disorders (5)(6)(7). ALDH1A1 overexpression has been found to play an important role in obesity, diabetes, and other diseases (8)(9)(10)(11)(12)(13).…”