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OCR for page 238
Bio~narkers arid Occupational Health: Progress arid Perspectives. 1995. Pp. 238-256
Xenobiotic-Metabolizing Enzymes in
Biomarker Research
Ffank J. Gonzalez
A large number of enzymes exist apparently for the sole purpose of me-
tabolizing foreign chemicals (or xenobiotics). It is believed that these
enzymes evolved primarily to inactivate or eliminate chemicals found
in dietary sources. Plants, for example, produce certain chemicals that
are toxic, and animals have enzymes that can degrade and inactivate
these toxins. Xenobiotic-metabolizing enzymes have historically been
grouped into two categories, the phase I or functionalizing enzymes and
the phase II conjugating enzymes (shown in Tables 1 and 2, respec-
tively). The cyto chrome P 450 and flavin- cont aining mono oxygenases
are the major phase I enzymes, while N-acetyltransferases, sulfotrans-
ferases, glutathione S-transferases, UDP-glucuronosyltransferases and
epoxide hydratases are among the primary phase II enzymes. The
xenobiotic-metabolizing enzymes function to inactivate, and in some
cases, activate therapeutically used drugs and, in this capacity, they are
of tremendous importance to the pharmaceutical industry. Interindi-
vidual differences in their expression and drug interactions due to over-
lapping metabolism of two or more drugs by the same enzyme form
can severely compromise drug therapy. Marked species differences in
the xenobiotic-metabolizing enzymes also complicate drug safety eval-
uations. Another important property of these enzymes is their ability
to be induced by xenobiotics, many of which are also substrates. It is
the interindividual differences in levels of expression of the xenobiotic-
metabolizing enzymes and their abilities to be induced by environmental
contaminants and dietary chemicals that render them important in the
field of biomarker research and development.
P450 cyto chromes are the major enzymes involved in drug, and,
in particular, carcinogen metabolism (Gonzalez, 1988; 1992; 1994b).
P450s exist as a large superfamily of proteins that are classified based
on their primary amino acid sequence similarities (Nelson et al., 1993~.
In mammals, several P450s are involved in specific reactions of steroid
biosynthesis and their expression is critical for survival. The vast ma-
238
OCR for page 239
XENOBIOTIC-METABOLIZING ENZYMES
239
jority of P450s found in the CYP1, CYP2, CYP3 and CYP4 families
metabolize xenobiotics (Gonzalez and Gelboin, 1993~. These enzymes
exhibit a high degree of species differences, and for this reason, human
P450s have been directly studied in recent years (Gonzalez, 1992~. A
partial list of human P450s that have been found to have high activities
toward known classes of carcinogens and mutagens is shown in Table 3.
TABLE 1. PHASE I ENZYMES
Enzymes Cosubstrates Multiple Forms
Alcohol dehydrogenases O2/2H yes
Aldehyde dehydrogenases O2/2H yes
Aldehyde oxidases O2/2H yes
Cytochromes P450 O2/2H yes
Flavin-dependent
monooxygenases O2/2H yes
Monoamine oxidase O2/2H no
Myeloperoxidase H2O2 no
Nitric oxide syntheses 2H yes
S-Oxidase no
Xanthine oxidase O2 no
Amidases H2O yes
A~lesterases H2O yes
Carboxylesterases H2O yes
Cholinesterases H2O yes
Epoxide hydratases H2O yes
Azoreductases 2H yes
Nitroreductases 2H yes
N-Oxide reductases 2H yes
In addition to their role in drug metabolism, xenobiotic-metaboli-
zing enzymes are also responsible for activating inert chemicals to their
electrophilic derivatives capable of binding to cellular macromolecules
and causing cell toxicity, death, and transformation. The principal ac-
tivating enzymes are the P450s, while the inactivating enzymes are the
transferases, although with specific procarcinogens/promutagens, the
transferases are also involved in activation. Human variability in levels
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240
FRANK J. GONZALEZ
of these enzymes is thought to be responsible for differential suscepti-
bility to chemical carcinogen-associated cancers. Indeed, recent studies
have indicated that levels of certain enzymes confer an altered risk for
cancer development and progression. Thus, different interindividual lev-
els of certain enzymes may be considered "biomarkers" for cancer risk.
Interindividual differences in enzyme levels are frequently due to the
existence of genetic polymorphisms. A number of polymorphisms have
been found and these can be diagnosed by polymerase chain reaction
(PCR) (Gonzalez and Idle, 1994~.
TABLE 2. PHASE II ENZYMES
Enzymes
Cosubstrates Multiple Forms
UDP-Glucuronosyltransferases Glucuronic acid yes
Sulfotransferases Sulfate yes
N-Acetyltransferases Acetate yes
Glutathione S-transferases Glutathione yes
N-Acyltransferases Amino acids yes
N,O, and S-Methyltransferase Methyl yes
Differences in levels of expression of xenobiotic-metabolizing en-
zymes can also be due to exposures to inducers. This property is an-
other area that is being exploited in biomarker research and develop-
ment. Environmental contaminants can result in an increase in levels
of P450s, notably CYPlA1. In humans, this P450 is markedly elevated
in the lungs, lymphocytes, and placentas of smokers. Efforts are under
way to determine whether CYPlA1 expression levels are also correlated
with lower level exposure to environmental and industrial chemicals
such as the polycyclic aromatic hydrocarbons, polychlorinated biphenyls
(PCBs), and related compounds.
Environmental contamination can be monitored by analysis of CY-
PlA1 expression in fish and rodents. Studies have shown that fish in
polluted waters have increased CYPlA1 and, in some cases, liver tu-
mors. Wild mice found at sites contaminated with PCBs were shown
to have high levels of these chemicals and increased CYPlA1 activities.
In conclusion, environmental contamination of certain potentially
harmful chemicals can be monitored by the induction of metabolic en-
zymes. Interindividual variation in levels of xenobiotic aetivating/inacti-
OCR for page 241
XENO BIOTIC-METAB OLIZING ENZYMES
241
vating enzymes may determine risk or susceptibility for chemical asso-
ciated diseases in humans.
TABLE 3. MAJOR HUMAN CARCINOGEN/MUTAGEN-METABOLIZING P450s
CYPl A l
CYPI A2
CYP2A6
CYP2E l
CYP3A4
Polycyclic aromatic hydrocarbons
Food mutagens, aflatoxins
Low molecular weight nitrosamines
Numerous low molecular weight cancer suspects
(ac~ylonitrile, benzene, nitrosamines, vinyl halides)
Aflatoxins, food mutagens, nitroaromatic hydrocarbons
BIOMARKERS FOR CANCER RISK
Genetic Polymorphisms
Since xenobiotic enzymes are responsible for either the activation
or inactivation of chemical carcinogens, it has not been overlooked that
their cellular levels may be associated with risk for cancer development
(Idle et al., 19929. Genetic polymorphisms exist in a number of phase I
and phase II enzymes (Figure 1~. Genetic polymorphisms can be deter-
mined by either using a metabolic probe drug or by a genotyping assay
such as PCR (Gonzalez and Idle, 1994~. Individuals lacking or having
low levels of a carcinogen-activating P450 or a carcinogen-inactivating
phase IT conjugating enzyme would be expected to be at increased risk
for cancer development.
CYP2D6 and Lung Cancer
The association of cancer risk with levels of xenobiotic-metabolizing
enzymes has been investigated. The CYP2D6 genetic polymorphism has
been the most extensively investigated with mixed results (Gonzalez,
1994c). This polymorphism can be determined by genotyping assays,
and it affects about 7.5 to 10% of Caucasians who possess two mutant
CYP2D6 alleles. In some studies, individuals lacking expression of the
enzyme due to the presence of mutant or variant alleles were found to
OCR for page 242
242
FRANK J. GONZALEZ
be at low risk for smoking-associated lung cancer. Other case-control
studies found no difference between the percentage of deficient subjects
in the cancer and control populations. Virtually all studies published to
date contain some flaw in their experimental design and therefore the
results and conclusions must be viewed cautiously (London et al., 1994~.
In order to determine whether the CYP2D6 polymorphism is associated
with cancer risk, larger and better controlled studies should be designed
in which genotyping tests are used to diagnose the presence of mutant
alleles.
PEE I
CO-SUBSTRATE
"2~
epoxide hydratases
'carbo~y-ester hydrolases
~~ arnidases
_ chollnesterases*
arylesterases*
H2 ~ azo-reductases
vitro -reductases
N-oxlde reductases
-I I _
mono-amine
oxidases
aldehyde
oxidase
ALDHI'
flavopro ein ADO'
mono -oxygenases*
PHASE II
CO-SUBSI'RATE
GLUCURONIC ACID
UDPGTs*
~ SULFATE
sulfotransferase`'
I AMINO ACIDS
N-acyl transferases
N-acetyl transferases*
| P450 mono-oxygenases
S-nxidas~ ~
O-methyl transferases
\ N-methyl transferases*
Methyl transferases*
_ GSH
GSTs
r Ten 1 n ~ r 7r
A A B *
A A B CDEF GH
* * **
FIGURE 1. Phase I and phase II xenobiotic-metabolizing enzymes. Those in
which polymorphisms are known or suspected are denoted by an asterix. Figure
reproduced from Idle et al. (1992) with permission from the authors.
CYPlA1 and Lung Cancer
The association of an allele of CYPlA1 and lung cancer in smok-
ers has also been investigated. CYPlA1 is the principal enzyme for
metabolic activation of polycyclic aromatic hydrocarbons (Nebert, 1989)
and is highly induced in lung tissues of smokers (McLemore et al., 1990~.
OCR for page 243
XENOBIOTIC-METABOLIZING ENZYMES
243
It was shown in early studies that the extent of CYPlA1 inducibility
was greater in lymphocytes derived from lung cancer patients (Kouri
et al., 1982~. Although a direct relationship between induction in lym-
phocytes and lung is assumed from animal studies, it has not been
demonstrated in humans. A correlation was found between cigarette
smoking-associated lung cancer and an CYPlA1 allele encoding a P450
with an Ile ~ Val amino acid change in Japanese (Kawajiri et al., 1993~.
The molecular basis of this association is unknown since the catalytic
activity or inducibility of this minor allele has not been examined. The
frequency of this allele is lower in Caucasians and in a limited study of
Norwegian cancer patients, there was no difference in allele frequency
between lung cancer patients and matched controls (Tefre et al., 1991~.
GSTM1 and Lung Cancer
A genetic polymorphism exists for a glutathione S-transferase GST-
M1 in which about half the population is deficient in this enzyme due to
a deletion of the gene (Seidergard et al., 1985; 1988~. Since this enzyme
is able to deactivate carcinogens such as arene oxides and polycyclic
aromatic hydrocarbons, a deficiency could result in cancer susceptibility.
As with the other cancer associations, the role of GSTM1 in cancer
remains controversial. An early study of 66 lung cancer patients and
controls revealed an underrepresentation of the active gene in patients
(Seidergard et al., 1986~. The association was confirmed in a study
of 176 Japanese patients (Kihara et al., 1994~. In nonadenocarcinoma
patients, the frequency of the null genotype was about 64(70 compared to
48% in matched controls. In adenocarcinoma patients, the frequency of
the deficiency was 545S, suggesting that only smoking-associated cancers
were affected by these polymorphisms. This was confirmed by a study
of the extent of smoking; the proportion of GSTM1 null genotype was
found to increase to 75~o in patients with the highest smoking index
(Table 4~. A similar association of the null alleles with lung cancer in
heavy smokers was found by others (Nazar-Stewart et al., 1993~.
In contrast to these results, others-have not found a difference in
the percentage of deficient subjects between lung cancer patients and
controls (Heckbert et al., 1992; Brockwoller et al., 1993~. However,
an increased risk was also found associated with the null genotype of
GSTM1 for colon cancer patients (Zhong et al., 1993~.
By analysis of P450 and GSTM1 genotypes, a strong association
with lung cancer risk was found in patients homozygous for the rare
OCR for page 244
244
FRANK J. GONZALEZ
CYPlA1 allele and the null GSTM1 suggesting that both P450s and
transferases are critical for human carcinogenesis (Hayashi et al., 1992~.
Follow-up confirmation studies by other groups have not been con-
ducted.
TABLE 4. PERCENTAGE OF HOMOZYGOUS NULL GSTM1 GENOTYPES IN MALE
SUBJECTS AS A FUNCTION OF TOBACCO SMOKE EXPOSURE
Smoking Index2
<800 800-1200 21200 Total
Kreyberg I 46 60 73 60
Squamous cell 50 55 72 60
Small cell 51 67 75 60
Kreyberg II
Adenocarcinoma 52 55 50 53
Control 45 43 48 45
~ Data taken from Kihara et al., 1994
2 Sum of cigarettes smoked per day x years of smoking
N-Acetyltransferase 2 and Cancer Risk
The N-acetyltransferases (NAT) have been shown to be involved in
both inactivation and activation pathways of carcinogen metabolism
(Figure 2~. The acetylation of amino groups results in an inactive
metabolite, while O-acetylation of an N-hydroxy group of certain aryl-
amine and heterocyclic arylamine carcinogens leads to an active elec-
trophilic derivative. Thus, it might be expected that the association of
the NAT enzyme with cancer susceptibility might be dependent on the
type of carcinogen.
N-Acetyltransferase 2 (NAT2) is polymorphic in humans and about
50~o of the population is deficient in the enzyme as a result of mutant
genes (Grant et al., 1992~. Early evidence showed an association be-
tween the deficiency and occupational bladder cancer (Cartwright et
al., 1982~. Others, using both phenotyping and genotyping to deter-
OCR for page 245
XENOBIOTIC-METABOLIZING ENZYMES
245
mine the NAT2 alleles, found no association between the deficiency and
increased risk of bladder cancer in workers occupationally exposed to
benzidine, a carcinogen that can be inactivated by NAT2 (Hayes et al.,
1993~.
o
11
,~ ~A3
< NAT2
CYP1A2
1
AH NAT2
POOH
· - <
- W~
1
o
'0- C CH3
~ AH
=^N<~)
FIGURE 2. Role of NAT2 in metabolism of arylamines. The enzyme can
carry out both N-acetylation inactivation pathways and O-acetylation activation
pathways. The N-acetoxy metabolite may also be hydroxylated by P450 which,
followed by migration of the acetyl group to the oxygen, can also lead to the
active carbonium ion.
In a study of smokers, the levels of 3- and 4-aminobiphenyl (ABP)
hemoglobin adducts, a biomarker for recent activation of ABP, were
OCR for page 246
246
FRANK J. GONZALEZ
higher in slow acetylators having deficient NAT2 alleles, showing a direct
correlation between the polymorphism and a biomarker for carcinogen
activation (Yu et al., 1994~. Higher levels of ABP adducts were found in
smokers. The finding was confirmed in Caucasians, Asians, and Blacks.
The latter race had the lowest proportion of NAT2-deficient subjects and
the highest level of adducts. Blacks also have the highest frequency of
bladder cancer, suggesting a causal association of NAT2 genotype with
cancer risk. This study was extended to assess the relationship between
NAT2 genotype and DNA adducts (Vineis et al., 1994~. Slow acetylators
were found to contain higher levels of aminobiphenyl-DNA adducts than
rapid acetylators. The effect of NAT2 genotype on both ABP and the
AB-DNA adducts became less significant in smokers. These studies
suggest that NAT2 genotype plays a role in carcinogen activation as
measured by protein and DNA adducts under conditions of low dose
environmental exposure.
The role of NAT2 in colon cancer has also been addressed. An
increased risk was found in individuals having rapid acetylation activity
and high CYP1A2 activity (Minchin et al., 1993~. This association
is opposite that found in bladder cancer indicating a role of NAT2 in
carcinogen activation. CYP1A2 is the primary enzyme responsible for
N-hydroxylation of arylamine carcinogens and heterocyclic arylamine
food mutagens. The N-hydroxy metabolite must be esterified by acetate
or sulfate in order to form the proximate metabolite capable of binding
to DNA. These data would suggest that the N-hydroxy metabolite is
formed in the liver by CYP1A2 and is transported to the colon where it
is activated by NAT2. Others found no difference in genotype frequency
and colon cancer association in Whites or Blacks and even suggested
that NAT1, which is not subject to genetic polymorphism, is the only
form expressed in human colon (Rodriguez et al., 1993~. Further studies
are warranted to determine the association of NAT2 genotype with colon
cancer.
In nonsmokers, 4-aminobiphenyl DNA adducts can be used as a
biomarker for both exposure to 4-aminobiphenyl and for NAT2 geno-
type. Aflatoxin B1 (AFB) DNA adducts in urine are a biomarker for ex-
posure to this human hepatocarcinogen (Groopman et al., 1994~. These
adducts were found to be higher in patients that ultimately get liver can-
cer. AFB is metabolically activated by cytochromes P450. Although
several human P450s can produce the active 8,9-epoxide metabolite
(Aoyama et al., 1990 a,b), CYPlA2 appears to be the P450 with the low-
est Michaelis-Menten constant Km for carrying out this reaction (Crespi
OCR for page 247
XENOBIOTIC-METABOLIZING ENZYMES
247
et al., 1991; Gallagher et al., 1994). A form of glutathione S-transferase
is capable of conjugating and inactivating the epoxide and studies in
rats have shown that induction of GST by the drug oltipraz protects
rats from AFB liver cancer (Kensler et al., 1987~. Perhaps this drug,
which also decreases AFB-DNA adducts in AFB fed rats, would be of
use in chemoprevention of hepatocarcinogenesis in areas of China and
Africa where this mold toxin is a serious contaminant of grains.
Estradiol Hydroxylase Activity and Breast Cancer Risk
Elevated estradiol-17B 16ar-hydroxylase activity in terminal duct
lobular units of human breast was found to be associated with increased
risk of breast cancer (Osborne et al., 1993~. These are the presumed
target sites of breast carcinogenesis. A four-fold to five-fold difference
was found in activity between controls and cancer patients. Despite the
age difference between the groups and the small sample size, these data
could indicate a very important enzymatic biomarker for breast cancer
risk. A polymorphism for this activity in humans has not been demon-
strated, nor has the P450 form involved in this oxidation been identified.
The possible mechanisms by which increased 16cx-hydroxylase could
be associated with increased cancer risk have been discussed (Nebert,
1993~. A P450 that metabolizes carcinogens could be involved since it
is well established that a P450 form capable of metabolic activation of
chemical carcinogens can also metabolize steroids and other chemicals to
stable metabolites. For example, CYP1A2, which metabolizes numer-
ous carcinogens and mutagens (Table 3) is an estrogen 2-hydroxylase
(Aoyama et al., 1990 a,b).
BIOMARKERS FOR CARCINOGEN EXPOSURE
Human Exposure
As noted earlier, 4-aminobiphenyl hemoglobin adducts and afla-
toxin B1 DNA adducts have been proposed as biomarkers for carcinogen
exposure. These biomarkers reflect recent exposure and their predictive
value for cancer cannot be assessed easily since cancer initiation in hu-
mans is likely to be followed by a long dormant period of perhaps 20
years. These biomarkers can, however, be used to determine current
environmental exposures.
Induction of CYPlA1 and CYPlA2 activity has been proposed as a
OCR for page 248
248
FRANK J. GONZALEZ
method to determine exposure to polycyclic aromatic hydrocarbon and
dioxin exposures. The mechanism for induction by this class of chem-
icals has been well studied (Gonzalez, 1994a). The heterodimeric Ah
receptor is required for binding the inducer ligand and transmitting the
signal for transcriptional activation to the nucleus. The receptor com-
plex binds to a regulatory element upstream of target genes and, through
a mechanism that is not completely understood, activates transcription.
The caffeine breath test was first developed to measure CYP1A2
activity in humans (Lambert et al., 1986~. In this test, the N-3 methyl
group of caffeine is labeled and after it is demethylated by the hepatic
P450, it can be measured as expired carbon dioxide. By using this
assay, higher levels of activity were detected in a cohort of Michigan
fishermen who were exposed to polybrominated biphenyls as compared
with matched controls (Lambert et al., 1990~.
In another study, CYPlA1 gene expression was monitored in hu-
man lymphocytes of railroad workers exposed to creosote in order to
determine exposure to polycyclic aromatic hydrocarbons (Cosma et al.,
1992~. This was accomplished by measuring mRNA levels. As compared
with matched controls, workers had a two-fold increase in CYPlA1
mRNA only when lymphocytes were collected in the summer (Table
5~. No significant differences were found between matched controls and
workers when activity was measured in the fall and winter. The level
of increase, although quite small as compared with fully-induced lym-
phocytes (Jaiswal et al., 1985), suggests that the polycyclic aromatic
hydrocarbons in the creosote volatilize in summer and contribute to
worker exposure. It is unclear how well the CYPlA1 mRNA induction
assays reflect the extent of exposure.
A reverse transcriptase-polymerase chain reaction method was de-
veloped to measure low levels of CYPlA1 mRNA (Vanden Heuvel et
al., 1993~. By this method mRNA could be readily measured in un-
stimulated lymphocytes. The high level of sensitivity may be of use in
measuring CYPlA1 expression in exposed populations.
Rodents as Biomarkers for Soil Contamination
Induction of CYPlA1 activity has been used to determine exposure
of mice at polychlorinated biphenyl (PCB) contaminated reference sites
(Lubes et al., 1992~. The levels of activities in individual mice were
correlated with hepatic PCB burdens. The increased activities were also
reflected in higher levels of CYPlA1 protein. These data suggest that
OCR for page 249
XENOBIOTIC-METABOLIZING ENZYMES
249
indigenous induction of mouse CYPlA1 may be employed as sensitive
biomarkers of environmental exposure to PC-Bs. Based on laboratory
studies it was suggested that feral rats may be even more sensitive than
mice for monitoring PCB exposure (Novak and Qualls, 1989; Lubet et
al., 1992~.
TABLE 5. EXPRESSION OF THE CYPlA1 GENE IN PERIPHERAL LYMPHOCYTES
OF CREOSOTE EXPOSED RAILROAD WORKERS
Season
Summer
Fall
Winter
mRNA Level
Controls Worker Workers/Controls
3.1 5.7 1.9
3.1 3.8 1.2
4.9 3.7 0.8
~ Reproduced from Cosma et al., 1992
Fish as Biomarkers for Water Contamination
CYPlA1 is inducible by polycyclic aromatic hydrocarbons (PAM)
and PCBs (Stegeman, 1989), and fish have been used as biological mon-
itors for PAH and PCB contamination (Payne et al., 1987; Goksoyr and
Forlin, 1992~. A number of studies have been conducted using fish to
monitor water pollution levels of CYPlA1 mRNA in livers of Atlantic
tomcod collected from two sites in the Hudson River in which the pol-
lution levels were higher than those found in a river in Maine (Kreamer
et al., 1991~. Placing the Hudson River fish in an aquarium resulted
in a loss of mRNA content which reached basal levels in 5 days. The
fish could be re-induced by laboratory exposure to sediment from a con-
taminated site. These studies demonstrate the ability of this species to
serve as an environmental monitor of aquatic pollution.
Studies have also been carried out analyzing Tilapia, a hearty fish
that is able to live in the heavily polluted Damsui River in northern
Taiwan. Fish collected in a particularly polluted upstream region of the
river had higher levels of CYPlA1 (Figure 3) and its associated activi-
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250
FRANK J. GONZALEZ
ties than Tilapia collected at a non-polluted downstream site (Ueng et
al., 1992; 1994~. Administration to fish in a laboratory aquarium of
sediment taken from polluted sites of the Damsui also markedly induce
CYPlA1 activity.
._
A_ _.
3MC U U U L L L
TILAPIA
FIGURE 3. Western blot analysis of the CYPlA1 protein in livers of the fish
Tilapia treated with 3-methylcholanthrene (3MC) or harvested from upstream
clean water (U) or downstream dirty water (L). Data taken from Ueng et al.
(1992) with permission from the authors.
Fish have been used to monitor inducers in paper mill effluents
(Mather-Mihaich and DiGiulio, 1991; Adams et al., 1992~. CYPlA1
was found to be induced by as little as a 10% diluted effluent (Mather-
Mihaich and DiGiulio, 1991~. Inducers found in effluent collected in
April were more potent than those collected in August. The chemicals
in the effluent causing the inducing effects are unknown.
OCR for page 251
XENOBIOTIC-METABOLIZING ENZYMES
REFERENCES
251
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Representative terms from entire chapter:
cancer risk
