J. Russo et al., IDENTIFICATION OF 4-(N,N-DIPROPYLAMINO)BENZALDEHYDE AS A POTENT, REVERSIBLE INHIBITOR OF MOUSE AND HUMAN CLASS-I ALDEHYDE DEHYDROGENASE, Biochemical pharmacology, 50(3), 1995, pp. 399-406
As the physiologic roles for the different classes of aldehyde dehydro
genase (ALDH) enzymes are elucidated, the identification of specific,
reversible inhibitors becomes of great pharmacologic interest. Previou
s structure-function studies identified dialkylamino substituted benza
ldehyde compounds as a novel class of reversible inhibitors of class I
ALDH. To examine further structural requirements for inhibition, we t
ested a series of 4-(N,N-dialkylamino)benzaldehyde analogs as inhibito
rs of propanal oxidation by mouse liver and human erythrocyte class I
ALDH. 4-(N,N-dipropylamino)benzaldehyde (DPAB) was identified as the m
ost potent, reversible inhibitor of propanal oxidation by class I ALDH
in spectrophotometric enzyme assays. In kinetic studies, DPAB showed
mixed-type inhibition with respect to the aldehyde substrates propanal
, phenylacetaldehyde, benzaldehyde, and aldophosphamide. DPAB exhibite
d uncompetitive inhibition with respect to the cofactor NAD. Inhibitio
n constants (K-i) for DPAB, estimated from Dixon plots, were 10 nM (pr
opanal) and 77 nM (phenylacetaldehyde) for mouse ALDH and 3 nM (propan
al) and 70 nM (phenylacetaldehyde) for human ALDH. These K-i values ar
e 100-fold lower than those reported for class I specific inhibitors.
At low (<1 mu M) DPAB concentrations, inhibition of propanal and aldop
hosphamide oxidation was > 75%, whereas inhibition of benzaldehyde (32
%) and phenylacetaldehyde (19%) oxidation was reduced markedly. These
results indicate that DPAB exhibits potent, reversible inhibition of m
ouse and human class I ALDH. The degree of inhibition was highly depen
dent on the structure of the aldehyde substrate.