Carcinogenesis vol.21 no.3 pp.
345–351, 2000
Metabolism of chemical carcinogens
F. Peter Guengerich
Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt
University School of Medicine, 638B Medical Research Building I, 23rd
Avenue South at Pierce, Nashville, Tennessee 37232-146, USA
Email: guengerich@toxicology.mc.vanderbilt.edu
The transformation of chemicals is important in carcino-
genesis, both in bioactivation and detoxification. Major
advances in the past 20 years include appreciation of the
migration of reactive electrophiles, the ability of Phase II
conjugating enzymes to activate chemicals, understanding
of the human enzymes, the realization that DNA modifica-
tion can result from endogenous chemicals, and the demon-
stration that cancers can result from the metabolism of
chemicals to non-covalently bound products. Pathways of
transformation in which major insight was gained during
the past 20 years include nitropolycyclic hydrocarbons,
polycyclic hydrocarbons and their diols, vinyl halides and
dihaloalkanes. Advances in analytical methods and recom-
binant DNA technology contributed greatly to the study of
metabolism of chemical carcinogens. Major advances have
been made in the assignment of roles of individual enzymes
in reactions. The knowledge developed in this field has
contributed to growth in the areas of chemoprevention,
molecular epidemiology and species comparisons of risk.
Some of the areas in which future development relevant to
carcinogen metabolism is expected involve pathways of
transformation of certain chemicals, regulation of genes
coding for many of the enzymes under consideration and
genomics.
Introduction
The discussion of the metabolism of carcinogens will be
focused largely on the enzymes involved in the activation and
detoxification of these chemicals. The basis of chemical
reactivity of activated carcinogens with DNA will not be
discussed per se. Most of the basic enzymatic transformations
of chemical carcinogens were already known in 1980
(1–3). However, most of the enzyme systems were not well
characterized and very little information existed regarding
individual enzymes within groups.
Highlights of metabolism research, 1980–2000
General concepts
Many of the general concepts regarding bioactivation, detoxi-
fication and genotoxicity had already been developed by Miller
and others (4,5). However, at least four major new concepts
regarding metabolism were developed during the past 20 years.
(i) ‘Reactive intermediates’ do have finite stability and can
travel limited distances to alkylate DNA. In the 1970s a view
Abbreviations: GSH, glutathione; P450, cytochrome P450; PBPK, physio-
logically-based pharmacokinetic (models).
© Oxford University Press
had developed that ‘activated carcinogens’ were so reactive
that they could not diffuse very far. This view led to the
hypothesis that only nuclear enzymes could be involved in the
activation of carcinogens (6). Subsequent work showed that
products reactive with DNA could be generated in hepatocytes
and be trapped outside the cells, e.g. with polycyclic hydrocar-
bons, nitrosamines and vinyl halides as the substrates (7–9).
Furthermore, i.p. injection of a benzo[a]pyrene diol epoxide
into pre-weanling mice generated lung tumors (10), arguing
that distribution could be widespread even with a compound
having a 30 s half-life.
(ii) ‘Phase II’ enzymes involved in conjugates are not only
protective but also activate chemical carcinogens. An example
is glutathione (GSH) transferase, which activates 1,2-dihalo-
ethanes (11,12). These enzymes can also activate other chem-
icals (13,14). Examples of roles of bioactivation are also
known for N-acetyltransferase (15), UDP-glucuronosyl trans-
ferase (16), sulfotransferase (17) and other Phase II reactions.
During the past 20 years evidence has been obtained for roles
of kinases in activation of chemical carcinogens (18).
(iii) Humans generally form the same DNA (and RNA and
protein) adducts as animal models. Twenty years ago this was
still a hypothesis but has now been clearly demonstrated in
many cases (19). Further review is beyond the scope of this
review and more relevant to another (20). The point is that
the same metabolic pathways are also important in humans
and animals; generally the major differences are quantitative.
(iv) DNA adducts can be generated by the metabolism of
‘endogenous’ chemicals. Key examples here are the generation
of DNA adducts from products of lipid peroxidation (21,22),
estrogens (23,24) and some other ‘endogenous’ materials.
(v) Metabolism of chemicals to unreactive, non-genotoxic
products can be an important issue in tumorigenesis, at least
in animal models. A classic example is the oxidation of 2,2,4-
trimethylpentane to an alcohol, which is stable but is complexed
with α2u-globulin to produce male rat kidney tumors (25).
Development of pathways of metabolism of carcinogens
Many of the pathways we accept today were already established
by 1980. For instance, the bay-region diol epoxide pathway
for polycyclic hydrocarbons, the N-hydroxylation of arylamines
followed by addition of a leaving group, and the α-
hydroxylation of N-nitrosamines were generally accepted path-
ways (26). However, some reactions had not been established
yet. One important group of carcinogens, the heterocyclic
amines, has been studied extensively only in the past 20 years,
but the pathways of metabolism are largely identical to those
established for aryl amines (1). Some of the newer pathways
for carcinogen metabolism include the following.
Nitropolycyclic hydrocarbons
These are of considerable interest because of their unusually
high bacterial mutagenicity (27) and potential activity in some
animal tumor models (28). Activation involves both diol
epoxide pathways and reduction to aryl hydroxylamines
(29,30). Redox cycling can occur with some of the nitro
345
F.P.Guengerich
compounds, at least monocyclic, to yield nitro anion radicals
and superoxide (31). P450s are involved in the oxygenation
reactions but a number of redox-active enzymes can participate
in activation (and detoxification) of nitro groups via reduc-
tion (32,33).
Oxidation of polycyclic hydrocarbon diols
One transformation that was not recognized until the 1980s was
the oxidation of trans-dihydrodiols of aromatic hydrocarbons to
o-catechols by dihydrodiol dehydrogenase [EC 1.3.1.20] (34).
These enzymes are members of an aldo-keto reductase super-
family and also have activities toward hydroxy steroids. The
oxidation suppresses the formation of carcinogenic dihydrodiol
epoxides; conversely, the catechols may oxidize (enzymatically
or non-enzymatically) to o-quinones and cause damage by
reaction with macromolecules or through generation of reactive
oxygen species (35,36).
Vinyl halides
In 1980 the metabolism of vinyl halides was understood
only in terms of epoxidation. Studies in this laboratory with
trichloroethylene (37) and vinylidene chloride (38) established
stepwise oxidation and 1,2-shifts as an explanation for the
products. This mechanism, with hydride migration, is generally
viewed as a part of the oxidation of terminal olefins (with
an aldehyde product) (39,40). Reactive haloacyl halides are
produced (41); the relevance of these and the epoxides them-
selves to genotoxicity remains to be established.
Dihaloalkanes
In 1978 Rannug reported the GSH-dependent activation of
1,2-dichloroethane (11). This pathway is now well-established,
with an episulfonium ion intermediate (42) and several charac-
terized DNA adducts (43). The general pathway has been
extended to dihalomethanes, although very limited information
is available about DNA adducts (44). The same pathway
appears to apply to trihalomethanes (45).
Development of analytical methods
Although many of the basic methods existed in 1980, the past
two decades have seen an explosion of capability in two
major areas.
Analytical chemistry
The first area involves chromatography and spectroscopy.
HPLC has been developed as a necessary technique in the area.
Capillary electrophoresis and other new separation techniques
have potential. NMR and mass spectrometry were already very
important in 1980 but today both methods have much greater
resolution and sensitivity and are coupled on-line with HPLC.
Other spectroscopic methods such as fluorescence (46) have
been applied to DNA adduct studies. 32P-post-labeling was
developed as a method of DNA adduct analysis by Randerath
(47) and has been integrated into metabolic studies, although
this method may ultimately be replaced by mass spectrometry
methods.
Recombinant DNA technology
These approaches were in their infancy in 1980. In 1982
the first P450 cDNA sequence was published (48), and the
characterization of the enzymes involved in carcinogen meta-
bolism would have been impossible without these methods.
Scarce proteins can be identified, characterized, and produced
in large amounts.
As an aside, it should be emphasized that human tissue
samples are now much more readily available than in 1980
346
and have been invaluable in extending work from animal
models to humans.
Characterization of roles of individual enzymes in carcinogen
metabolism
By 1980 many of the general concepts about the significance
of enzymes in carcinogen metabolism had been developed, at
least in principle. For instance, enzymes such as P450 were
known to be inducible (49), enzymatic differences could be
used to explain variable susceptibility of individual animals to
carcinogens (50), and some evidence for P450 polymorphism
as a risk factor in lung cancer had been presented (51).
Enzymology had been used successfully to address issues
regarding the existence of multiple enzyme forms within some
multi-gene families (52–56).
Protein chemistry and, later, molecular biology techniques
were developed to characterize the enzymes involved in
carcinogen metabolism, both in terms of the enzymology and
also regulation of gene expression. This work was done
with experimental animal models and, most importantly, with
humans. Today there is a reasonably good understanding
of many individual enzymes (e.g. individual P450s, GSH
transferases, etc.) in terms of their concentrations in various
human tissues, the extent of variability among humans, and
the involvement of these enzymes in particular steps in
metabolism of chemical carcinogens (57). The approaches
are used rather routinely and many have been relatively
straightforward, although the overall significance of a particular
reaction to tumorigenesis may not always be clear. In the past
few years, animals in which particular enzymes have been
‘knocked out’ have been used in cancer studies to define the
roles of individual proteins in the overall processes of toxicity
and carcinogenesis (58,59).
Inter-individual variation in the enzymes involved in carcino-
gen metabolism is now extensively studied. To date there has
been impressive success in the application of information
about human P450s in the development of new drugs in the
pharmaceutical industry (57). There is optimism that such
approaches will also be productive in the prediction of cancer
risks due to inter-individual variations in enzymes. The
National Institute of Environmental Health Sciences has begun
an Environmental Genome Project, in which the long-term
goal is to associate risks with polymorphisms of the genes
involved in carcinogen metabolism, as well as others (60).
The overall appreciation, characterization and organization of
information about individual genes has developed dramatically
since 1980.
Development of approaches to chemoprevention
Chemoprevention is discussed in another article in this issue
(61). The strategy of inducing ‘Phase II’ conjugating enzymes
was already in place before 1980 (62), but knowledge about
the regulation of conjugating enzymes (63) and the inhibition
of P450s (64–66) has been integrated. Also of interest, however,
are reports that some of the chemopreventive agents can
increase the toxicity, or at least DNA adduct formation, by
inducing the conjugating enzymes (67,68).
Development of in vitro genotoxicity assays
These cellular systems are very useful both in basic studies
on roles of enzymes in activation/detoxification and in practical
work on new chemicals, etc. The majority of the major systems
used today was done before 1980. During the past decade many

improvements in the systems have been made, particularly in
terms of integration with enzyme systems of mammalian origin.
Purified enzymes and human microsomes have been added
to Salmonella typhimurium-based systems, both in the classic
Ames’ reversion assay (69) and an SOS response-based colori-
metric assay (70), in order to define roles of individual
enzymes. Another approach is to express individual enzymes,
or sets of enzymes, and reporter genes within cells. Such
approaches have been utilized with mammalian cells (71) and
bacteria (72). Both S.typhimurium and Escherichia coli-based
systems with P450s have been used (73–75).
Development of predictions for humans based upon species
comparisons
One of the problems with in vitro results obtained in some of
the systems described above is that the relevance of metabolism
in different tissues may be difficult to relate to in vivo problems,
e.g. cancer. One approach is the use of PBPK models, which
have been developed mainly in the past 20 years. A common
strategy is to: (i) define specific enzymatic steps of major
relevance to bioactivation and detoxification; (ii) identify the
most important tissues, in terms of metabolism and as targets
for tumor development; (iii) collect data on rates of all relevant
enzymatic transformations in vitro, with tissues of interest
both from humans and experiment models; (iv) if possible (i.e.
with reasonably weak cancer suspects such as industrial
solvents), validate the model in humans with low exposures;
and (v) on the basis of comparisons and predictions about the
effective concentration of the activated carcinogen delivered
at the target site in humans and animals, compare the risk of
concentrations of the chemical to humans to those known to
produce tumors in the experimental animal models (76,77).
This strategy has been used with information about lung and
liver measurements of CH2Cl2 metabolism by P450 2E1
and GSH transferase T1 (78), and as a consequence the
Environmental Protection Agency revised its exposure limit
upwards.
Current and future issues in metabolism of chemical carci-
nogens
Although much progress has been made in the past 20 years
and the field has matured, there are a number of remaining
challenges that must be considered. These involve the general
significance of the field and the basis for development of
related areas, such as genomics.
Relevant pathways need to be established for more chemicals
Despite all of the knowledge of pathways obtained in the past
half-century or more (79), the reactions remain to be established
in many cases. Some notable examples include the GSH
conjugation of trihalomethanes found in drinking water (45)
and the oxidation products of trichloroethylene, at least those
that are involved in reactions with macromolecules (9) [a
separate issue is the contribution of an alternate, GSH-depend-
ent pathway to activation (80,81)]. Even after many years of
research on polycyclic hydrocarbons, controversies exist about
the contribution of a radical pathway (82,83) and suggestions
of ‘poly’ oxidized products have been proposed (84). Another
issue involves the chemical characterization of the DNA
adducts generated by oxidations of several compounds by
peroxidases (e.g. myeloperoxidase, cyclooxygenase, etc.) (85).
Basic enzymology
Understanding mechanistic details of one transformation is
critical in making predictions about others. Much remains to
Metabolism of carcinogens
be understood about most of the enzymes under consideration
here (for recent review on the enzymes of interest, see ref.
86). The questions relate to both structure and catalysis (which
are not unrelated). With some of the enzymes, the availability
of crystal structures has facilitated progress (87,88); more are
needed. Enzymology issues with practical implications include
the question of whether P450s can catalyze 1-electron oxidation
of polycyclic aromatic hydrocarbons (82). This hypothesis
seems reasonable but has been difficult to address (89). The
meaning of Km in most of the enzymatic transformations is
not well understood (90–92); what does this value mean when
incorporated into PBPK models (93)?
Genomics
Genomics is a popular field today, and in the area of carcinogen
metabolism there is much anticipation that genetic differences
in the enzymes of interest will be associated with major
differences in cancer risk. Two major issues must be addressed
in the course of a massive study. The first is the identification
of the major allelic variants of the genes (that code for the
enzymes under consideration). This effort will require large-
scale sequencing efforts. In some enzyme families not all of
the individual genes have been identified yet (94,95).
The second issue is functional analysis. One approach to
assessing the significance of genetic variations is to go directly
to epidemiological correlations. However, the danger of going
directly to such associations in the absence of basic scientific
information has been demonstrated in the work with P450
2D6 (96,97). A logical approach is development of functional
analysis systems, in which allelic variants of enzymes can be
expressed and examined for parameters relevant to metabolism
of relevant carcinogens. (For further discussion of the complex-
ity and relevant issues, see ref. 60.)
Regulation of expression of enzymes
In a sense, most of the progress made in the regulation of the
enzymes of interest has been made in the past 20 years,
primarily because of the development of useful methodology.
Today, much is known about the systems, but even more
questions remain. In many cases, even the primary responsive
elements (receptors) remain to be identified and fully character-
ized [e.g. antioxidant response element system (98–100)].
Recent progress in the characterization of barbiturate and
other drug-binding receptors has been promising (101,102).
However, as work has proceeded with the elucidation of
elements involved in gene regulation, so has the appreciation
of the complexity of the systems. As an example, consider
the Ah locus. The Ah receptor has now been extensively
characterized but the list of involved partners continues to
grow (103–107) and definition of the role of each component
remains challenging.
A need exists for more understanding of mechanisms of
regulation of enzymes involved in carcinogen metabolism. Just
as important is an understanding of the influence of modulation
on carcinogenesis and toxicity. For instance, we are still not
in a position to provide an explanation for the carcinogenicity
and toxicity of dioxins (108). Without such understanding,
efforts to compare risk among species (e.g. humans) are
deficient (109). Does induction of Ah-linked genes really
imply increased risk from a chemical? Although regulatory
agencies are concerned because of the example of dioxin, the
answers still remain equivocal or, at the least, dependent upon
the particular model under investigation (110,111). Concerns
347
F.P.Guengerich
also exist about the significance of induction by barbiturates
and peroxisome proliferators to carcinogenesis (112).
Relevance to biomarkers and molecular epidemiology
The basic question is whether high or low activity of a
particular enzyme is related to a change in risk. This type of
work has become popular and there is good precedent for
success in the paradigms of drug metabolism and P450 (57).
Programs such as the Environmental Genome Project have
been set up to evaluate the contribution of gene polymorphisms
to various risks. Many issues need to be addressed, and there
is considerable room for innovative approaches. These include
better technology for high-throughput screening and also
‘functional genomics’ (i.e. approaches to determining the effect
of a genetic change on the enzymatic or other function of the
involved proteins) (60,113,114). Another issue in this area is
that of tissue localization and relevance to exposure. For
instance, we have made the point that the epoxidation of
aflatoxin B1 in the small intestine should be considered a
detoxification event, in that it diverts the mycotoxin (from the
liver) to cells that are readily sloughed (115). The issue of
tissue localization is a problem in that it shifts the field to
measurement of RNA and proteins, which must be excised
from humans in order to make analyses. A related issue with
polymorphisms is with genes that are not expressed in target
tissues. Consideration of distribution kinetics of carcinogens
and active metabolites and PBPK modes is needed (vide supra).
Assays with mixtures
Almost all of the experiments in the chemical carcinogenesis
literature have been done with single compounds. This reduc-
tionist approach is not inappropriate and is certainly com-
mended for understanding basic mechanisms. However, real
exposure situations all involve mixtures and the approaches to
dealing with these are difficult. As an example from our own
research, consider work on the genotoxicity of tobacco smoke
condensate components (116). The work was difficult because
of the extremely inhibitory effect of tar components on P450
enzymes. What does this mean in terms of issues with smoking?
The literature contains considerations of strategies. More
insight will be needed in this area, particularly as scientists
try to relate work on carcinogen metabolism to molecular
epidemiology and practical human issues.
General relevance of carcinogen metabolism to cancer
This issue was addressed in a 1988 review (2). There is ample
evidence in experimental animal models that altered carcinogen
metabolism can have dramatic effects on tumor incidence
(111,117). The concept that enzyme differences in humans
can alter xenobiotic disposition and effects has very good
precedence in the pharmaceutical industry, as mentioned earlier.
Therefore, there is great hope that similar effects will be seen
with cancer. However, the epidemiology results to date have
not been strong. Although the association of P450 2D6 with
lung cancer has been studied for many years, neither consistent
epidemiology nor an experimental basis of a causal relationship
have resulted (96,97,118). Similar problems have been encoun-
tered with GSH transferases M1 and P1 (119,120). Although
there have been some reports of altered cancer incidence
related to P450s 1A1 and 1B1 (121,122), the results cannot
be interpreted in terms of any dramatic experimental differences
between the allelic gene products (123–125). The evidence
regarding N-acetyltransferase may be more compelling
(126,127). One of the major problems in doing epidemiology
348
studies of this type is assessment of the actual chemical
exposure, whether an endogenous or xenobiotic chemical.
Linking variations in enzyme expression and catalytic activity
to the endpoint of human cancer (128) will remain a challenge
for at least part of the next 20 years.
Acknowledgements
I would like to dediacte this article to Prof. James A.Miller, who, with his
late wife Elizabeth, really developed this area (4,49,79). I also thank Dr Fred
Kadlubar for his comments on the manuscript. Work in the author’s laboratory
was supported in part by funds from the USPHS (R35 CA44353 and
P30 ES00267).
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