Springer, Encyclopedic Reference Of Cancer (2001) Ocr 7.0 Lotb.pdf

248 Detoxification
modifications by the phase 1 CYP isoenzymes
before serving as substrates for the
phase 2 enzymes (3). Alternatively, some xenobiotics
do not require modification by
phase 1 enzymes before metabolism by
phase 2 enzymes, and others are subject to
modification by more than one phase 2
drug-metabolizing enzyme. As a result of
differences in drug metabolism, the group
of enzymes catalyzing reduction of hydrolysis
reactions (e.g. ! aldehyde dehydrogenase
(ADH), ! aldo-keto reductase (AKR), ! epoxide
hydrolase (EPHX) and ! NAD(P)H-quinone
oxidoreductase (NQO)) are variously referred
to as phase 1 or phase 2 detoxication,
depending on the individual xenobiotic
being considered and the preferences of research
workers (4). Clearly, these enzymes
provide a highly flexible metabolic defense
that has evolved to protect against a diverse
spectrum of chemicals.
* Finally, phase 3 of detoxication involves
ATP-dependent elimination of the parent
compound or modified xenobiotic by proteins
that are drug efflux pumps (e.g. ! multidrug
resistance protein (MDR) and ! multidrug
resistance-associated protein (! MRP))
(5, 6). As a consequence of the combined actions
of phase 1 and phase 2 enzymes, a diverse
spectrum of xenobiotics acquires a
limited number of molecular `tags' (i.e. acetate,
glutathione, glucuronide or sulphate
moieties) that are recognized by the MRP
trans-membrane pumps. Furthermore, the
xenobiotic metabolites produced by phase
1 and phase 2 are usually more soluble,
and easily excreted, than the parent compound.
Whilst the ability of CYP to oxidize xenobiotics
is generally desirable, as it facilitates further
metabolism and elimination of harmful chemicals,
it can sometimes result in the generation
of highly reactive products that may not be
readily detoxified (3). In such instances, modification
of intracellular macromolecules will
occur resulting in necrosis, ! apoptosis or malignant
! transformation. As an example of the
interplay between toxification and detoxification
reactions, a scheme depicting metabolism
of ! aflatoxin B 1 (AFB 1), modification of macromolecules
by AFB 1 metabolites, and efflux of
the AFB 1-glutathione conjugate from a cell is
shown in the illustration (Fig.).
Genetic variation
Numerous proteins have envolved that detoxify
drugs, and certain of the families listed above
comprise over twenty genes. In total, the
Detoxification. Fig. ± Detoxification pathways for
aflatoxin B1. The mycotoxin is converted to the ultimate
carcinogen AFB1-8,9-epoxide, by the actions
of the hepatic phase 1 CYP enzyme system. The
epoxidated AFB1 is highly reactive, and if it is not
detoxified it will form DNA adducts that may cause
hepatocarcinogenesis. The phase 2 GST enzymes can
achieve detoxification of this unstable intermediate,
and the resulting AFB1-glutathione conjugate is
eliminated from the liver cell by MRP. In addition,
AFB1-8,9-epoxide can rearrange to form a dialdehyde-containing
metabolite which will covalently
modify proteins by forming Schiff's bases. The dialdelhyde
can be reduced by phase 2 AKR to yield a
dialcohol that may be a substrate for SULT or UGT
before being transported out of the cell, presumably
by MRP.