functional ALDH genes (Vasiliou and Nebert, 2005). In animal models, some
of the ALDHs are inducible by barbiturates or by ligands of the Ah receptor,
for example, ALDH3 (Takimoto et al., 1992). A number of polymorphisms
have been identified that result in attenuation of catalytic activity; as with
ADH, many of these show racial linkages.
The reaction mechanism is ordered bi-bi, with NAD(P)+binding first, and
then, NAD(P)H being the last product to leave the enzyme (Petersen and
Lindahl, 1997). Inhibitors include disulfiram and some others that overlap
with ADH and P450 2E1, two other enzymes that process ethanol and
acetaldehyde.
One substrate is trans, trans-muconaldehyde, an oxidation product of
benzene. Examples of drugs in which ALDH has a major contribution are
cyclophosphamide and procarbazine. Other substrates include 4-hydroxynone-
nal and other products of lipid peroxidation (Petersen and Lindahl, 1997).
2.6 Reduction
2.6.1 P450, ADH
The general tendency is for these enzymes to oxidize substrates, but they also
catalyze reductions.
The reaction with ADH is relatively straightforward and simply a 2e
reduction of an aldehyde or imine.
RCHOþNADðPÞHþHþ!RCH 2 OHþNADPþThe P450-catalyzed reductions are certainly not as common as the
oxidations, and the question can be raised as to why these occur at all, given
the proclivity of ferrous P450 to react with O 2. However, some parts of the
body have low oxygen tension, such as the venous sections of the liver, and the
reductions can be documented. Some of the reductions that have been
documented to involve P450s include (Baker and Van Dyke, 1984; Wislocki
et al., 1980):
RNO 2 !RN¼O
RN¼O!RNHOH
RNHOH!RNH 2
R 3 NþO!R 3 N
RN¼NR^0 !RNH 2 þH 2 NR^0
CCl 4 !CCl 3 þClBenzo[a]pyrene 4,5-oxide!benzo[a]pyrene
Halothane!2-Cl-l,l,l-F 3 ethane + 2-C1-1,l-F 2 ethylene26 OXIDATIVE, REDUCTIVE, AND HYDROLYTIC METABOLISM OF DRUGS