Inactivation of Aldehyde Dehydrogenase by Disulfiram in the Presence and Absence of Lipoic Acid or Dihydrolipoic Acid: An in Vitro Study

Abstract

The inhibition of aldehyde dehydrogenase (ALDH) by disulfiram (DSF) in vitro can be prevented and/or reversed by dithiothreitol (DTT), which is a well-known low molecular weight non-physiological redox reagent commonly used in laboratory experiments. These observations inspired us to ask the question whether the inhibition of ALDH by DSF can be preserved or abolished also by dihydrolipoic acid (DHLA), which is the only currently known low molecular weight physiological dithiol in the body of humans and other animals. It can even be metaphorized that DHLA is an “endogenous DTT”. Lipoic acid (LA) is the oxidized form of DHLA. We investigated the inactivation of ALDH derived from yeast and rat liver by DSF in the presence or absence of LA or DHLA. The results clearly show that DHLA is able both to restore and protect ALDH activity blocked by DSF. The proposed mechanism is discussed.

Can Lipoic Acid Attenuate Cardiovascular Disturbances Induced by Ethanol and Disulfiram Administration Separately or Jointly in Rats?

“…On the other hand, the results indicating that LA is an inhibitor of ALDH activity turned out to be very surprising (Table 2), the more so that our previous observations in vitro indicated that the presence of LA or DHLA had no effect on the activity of yeast ALDH. Those observations demonstrated also that DHLA but not LA could protect ALDH against DSF-induced blockade, while neither LA nor DHLA were able to restore the ALDH activity when it already had been inhibited by DSF [23]. However, it should be noted that it is increasingly more frequently underlined that biological effects of LA obtained in vitro often differ from those observed in vivo which was largely unnoticed until recently [24, 25].…”

The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver

“…5 a demonstrates that both metabolites - HO8IM and COOH7IM - were produced by HepaRG cells after addition of M8OI to cultures. Addition of either the alcohol dehydrogenase or acetaldehyde dehydrogenase inhibitors 4-methylpyrazole ( Bestic et al, 2009 ; Hartman et al, 2014 ) and disulfiram ( Bilska-Wilkosz et al, 2019 ) respectively resulted in higher medium levels of HO8IM and lower levels of COOH7IM metabolites compared to control cell cultures ( Fig. 5 a).…”

Is the mechanism of nitroglycerin tolerance associated with aldehyde dehydrogenase activity? A contribution to the ongoing discussion

“…That is why we decided to use the inhibitor of all ALDH isozymes, i.e. DSF, whose action is irreversible in vivo, and restoration of activity of all ALDH isozymes (including ALDH2), is only dependent on de novo protein synthesis, in contrast to in vitro conditions, where the mechanism of action of this inhibitor is completely different from the one in vivo (Bilska-Wilkosz et al, 2019a;Kitson, 1975;Shen et al, 2000;Vallari & Pietruszko, 1982).…”