Environmental Health Perspectives Volume
102, Supplement 6, October 1994
[Citation
in PubMed] [Related
Articles]
Species Differences in Metabolism of Heterocyclic Aromatic Amines, Human
Exposure, and Biomonitoring
Robert J. Turesky,1 Gian A. Gross,1 W.G. Stillwell,2
Paul L. Skipper,2 and Steven R. Tannenbaum2,3
1Nestec Ltd., Nestle Research Centre, Lausanne, Switzerland;
2Division of Toxicology, MIT, Cambridge, Massachusetts; 3Department
of Chemistry, MIT, Cambridge, Massachusetts
Abstract
Heterocyclic aromatic amines (HAAs) are animal carcinogens and suspected
human carcinogens which are formed in cooked foods at the low parts per
billion level. HAAs in cooked meats were purified by either immunoaffinity
chromatography or solid phase tandem extraction, which allowed for the simultaneous
analysis of 11 HAAs by HPLC. The metabolism of two prominent HAAs, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline
(MeIQx) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), was investigated
in animal models and in vitro with human tissues to develop strategies
for human biomonitoring. MeIQx and IQ are rapidly absorbed from the gastrointestinal
tract of rodents and transformed into several detoxification products which
are excreted in urine and feces. Metabolites result from cytochrome P450-mediated
ring oxidation at the C-5 position followed by conjugation to sulfate or
ß-glucuronic acid. Other major metabolites include the phase II conjugates,
N2-glucuronide and N2-sulfamate. A metastable N2-glucuronide
conjugate of the genotoxic metabolite of N-hydroxy-MeIQx was also
detected in urine and bile. The binding of both carcinogens to blood proteins
was low and suggests that human biomonitoring through protein adducts may
be difficult. These metabolic pathways exist in nonhuman primates and several
of these pathways also occur in vitro with human liver. The urinary
excretion of MeIQx in seven human subjects following consumption of cooked
beef or fish ranged between 2 and 22 ng in 12 hr when determined by negative
ion chemical ionization GC-MS. After acid hydrolysis of urine, the amount
of MeIQx increased 4- to 10-fold in 6 of the 7 subjects. These acid labile
metabolites were identified as the N2-sulfamate and N2-glucuronide
following column chromatography and HPLC purification. Thus, amine sulfamation
and N2-glucuronidation are important routes of detoxification
of MeIQx in rodents, nonhuman primates, and humans. -- Environ Health
Perspect 102(Suppl 6):47-51 (1994)
Key words: food mutagens, heterocyclic aromatic amines, metabolism,
human biomonitoring
This paper was presented at the Fifth International Conference
on Carcinogenic and Mutagenic N-Substituted Aryl Compounds held
18-21 October 1992 in Würzburg, Germany.
We would like to thank M.S. Ali and J. Richoz for their
aid in the analyses of HAAs in cooked foods and C. Leaf for her valuable
critiques on this manuscript. This work was partially funded (WGS, PLS,
and SRT) by NIH grants ES05622 and ES02109.
Address correspondence to R. J. Turesky, Nestec Ltd.,
Nestle Research Centre, Vers-chez-les-Blanc, 1000 Lausanne 26, Switzerland.
Introduction
More than a dozen heterocyclic aromatic amines (HAAs) have been identified
in cooked foods at the low part per billion level (1) and all HAAs
tested so far are carcinogenic in rodent bioassays (2). One of these
food-borne mutagens, 2 amino-3-methylimidazo[4,5-f]quinoline (IQ),
is also a potent hepatocarcinogen in nonhuman primates (3). Metabolic
studies with human tissues show that humans activate HAAs at appreciable
levels. Activities for some substrates are comparable to those observed
in rodents (4-8). Thus, despite the occurrence of HAAs in only trace
amounts, their presence in many common foods suggests that human exposure
can be significant and that HAAs may be involved in the etiology of human
cancers.
The risk evaluation of genotoxins such as HAAs is based on quantitative
estimates of exposure and on the formation of toxicologically active metabolites
in target tissues. In recent years, both DNA and protein adducts have been
used successfully as biologic markers to measure human exposure and to estimate
the formation of the genotoxic metabolites of a variety of environmental
and dietary carcinogens (9,10). The most direct evidence of recent
exposure and genetic damage is through the measurement of DNA adducts in
cells and their excretion products in urine; whereas measurement of protein
adducts may provide an index of long-term exposure over the lifetime of
the protein. Analysis of urinary metabolites of xenobiotics may also provide
important biologic data. For example, human acetyltransferase and cytochrome
P4501A2 metabolic phenotype activity can be determined by analysis of caffeine
metabolites in urine and may be used as biomarkers of cancer susceptibility
(11,12). The analysis of urinary metabolites of genotoxins, such
as HAAs, may also provide important information on the ability of humans
to metabolically activate or detoxify these procarcinogens and may aid in
risk evaluation. Our recent data on the quantification of HAAs in cooked
foods, the metabolism of IQ and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline
(MeIQx) in experimental animals, and our preliminary data on human metabolism
are presented in this article.
Methods
Quantification of HAAs in Cooked Foods
HAAs were isolated from cooked meats and fish by solid-phase tandem extraction
using an Extrelut-20 column in series with a propylsulfonic acid silica
cartridge and quantified with multiple internal standards(13,14).
HAAs were quantified by HPLC employing a Hewlett-Packard 1090M system containing
both a UV diode array detector and a fluorimeter. A Vydac 201HS52 narrow
bore reverse-phase column was used for increased sensitivity and resolution.
Metabolism Studies in Animal Models
Metabolism studies were performed with male Sprague-Dawley rats. MeIQx
was administered by gavage as its acetate salt. In some instances, animals
were pretreated with a single ip injection of Aroclor 1254 in corn oil 24
hr prior to dosing (15). Metabolites were isolated from biologic
fluids and reference standards were prepared either biosynthetically using
rat hepatocytes or through chemical syntheses (16 ). Urine and bile
were obtained from nonhuman primates undergoing carcinogen bioassays with
IQ and MeIQx (3) and metabolites were purified and spectroscopically
characterized as previously reported (17).
Metabolism Studies in Humans
Analysis of MeIQx and its metabolites in human urine was done by negative
ion chemical ionization gas chromatography-mass spectrometry (NICI-GC-MS)
after derivatization with 3,5-bis(trifluoromethyl)benzyl bromide
(18). Trideutero-labeled (N-Cd3)-MeIQx was used as an
internal standard. Each of the seven subjects consumed 1 lb (before cooking)
of panfried fish or beef. Urine collections were made 0 to 12 hr postmeal.
Aliquots of urine were analyzed for unchanged MeIQx before and after acid
hydrolysis (1 N HCl at 70°C for 6 hr) which cleaves the N2-glucuronide
and N2-sulfamate conjugates with quantitative recovery
of MeIQx (19). The samples, both nonhydrolyzed and acid hydrolyzed,
underwent solvent partitioning and immunoaffinity chromatography prior to
NICI-GC-MS analyses (Hewlett-Packard 5987 GC-MS system and an HP-1 capillary
column) (20). MeIQx and the deuterated internal standard were detected
and quantified by selective ion monitoring of the ions at mz 438 and mz
441, respectively (corresponding to the M-227 ions of the [di(3,5-(bis-trifluoromethyl)benzyl]
derivatives). The N2-sulfamate and the N2-glucuronide
were isolated from human urine as described (15) except that solid
phase extraction steps with both C-18 and aminopropyl resins were included
after the organic precipitation of urine. The urine extract was dissolved
in 30 ml 50 mM ammonium acetate, pH 6.8, and then applied to a Partisil
(C-18) column. After washing with this buffer, metabolites were eluted in
50% methanol and dried. The residue was dissolved in water, its pH adjusted
to 8.0 and then applied to a propylamine cartridge. The eluent was dried,
redissolved in 1 ml of 50 mM ammonium acetate (pH 6.8), diluted with 9 ml
acetonitrile and applied to the propylamine cartridge in normal phase mode.
The sulfamate was eluted with 30% ammonium acetate buffer and 70% acetonitrile
and then the N2-glucuronide was eluted with 50 mM ammonium
acetate containing 2% ammonium hydroxide (vol/vol). This extraction procedure
enabled partial separation of the N2-sulfamate from the
N2-glucuronide conjugate (20), which was verified
by HPLC (15) and by NICI-GC-MS.
Results
The solid phase tandem extraction procedure is highly selective for the
purification of HAAs and enables quantification at levels approaching 1
ppb. HAA content was determined in several cooked foods with this extraction
procedure and the data is presented in Table 1. The production of these
genotoxins in cooked foods varied greatly and depended on the type of meat,
cooking temperature and manner of preparation. High levels of HAAs were
also detected in cooking grill scrapings, which are often used as a gravy
base. A typical chromatogram of purified HAAs in from grill scrapings is
shown in Figure 1.
Figure 1. HPLC
analysis of heterocyclic aromatic amines in grilled meat residue. Inset
shows online UV spectra of MeIQx and PhIP along with reference standards.
MeIQx and IQ metabolism were investigated in animal models to develop
strategies for human biomonitoring. In the rat, MeIQx metabolism and disposition
were dependent upon dose and animal pretreatment with PCB. At the 20 mg/kg
treatment approximately 50% of the dose was excreted in urine within 24
hr while at the lowest dose tested 20 to 25% of the dose was recovered in
urine and the remainder recovered in feces (15). The 5 major metabolites
excreted in urine and bile are the sulfate and ß-glucuronic acid conjugates
of the 5-hydroxy derivative of MeIQx, the N2-glucuronide and
the N2-sulfarnate phase II conjugates, and the N2-glucuronide
conjugate of the procarcinogenic metabolite, N-hydroxy-MeIQx (Figure
2) (15). At the highest dose tested, N2-sulfamate
formation was the major route of detoxification and urinary elimination
of MeIQx in noninduced animals. However, other metabolic pathways, such
as 5-hydroxylation of MeIQx and N2-glucuronidation, were more
prominent both at lower doses and in animals pretreated with PCB (Figure
3). In animals treated with MeIQx at 0.01 mg/kg, each of the above metabolites
accounted for 0.5 to 4% of the total dose in urine whereas unmetabolized
MeIQx accounted for 0.5 to 2% of the dose. Notably, the formation and excretion
of the metastable N2-glucuronide conjugate of N-hydroxy-MeIQx
was relatively more important at low-dose exposure.
Figure 2. Structures
of the 5 major metabolites of MeIQx excreted in rat urine: N-(3-8-dimethylimdazo[4,5-f]quinoxalin-2-yl)sulfamic
acid (NSO3-); N2-(ß-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline
(N-Gl); N2-(ß-1-glucosiduronyl)-N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline
(HO-N-Gl); 2-amino-5-(ß-glucosiduronyloxy)-3,8-dimethylimidazo[4,5-f]quinoxaline
(5-O-Gl); 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline-5-yl sulfate
(5-OSO3-).
Figure 3. Percent
distribution of major urinary metabolites of MeIQx in rats as a function
of dose and cytochrome P450 induction with Aroclor 1254. (n=4 animals
per group, *p<0.05)
Urine samples (8 hr collections) from rats dosed with MeIQx (0.01 mg/kg)
were analyzed before (Figure 4) and after hydrolysis, which resulted in
cleavage of all the characterized metabolites. MeIQx recovery in urine after
acid hydrolysis increased from 2 to approximately 7% of the dose in non-induced
animals and from 0.5% to nearly 6% of the dose in PCB pretreated animals
(n=4 animals). This increase in MeIQx was commensurate to the amount
of cleaved sulfamate and N2-glucuronide. The 5-hydroxy
derivative of MeIQx and the genotoxic metabolite, N-hydroxy-MeIQx,
the initial hydrolysis product of the N-hydroxy-N2-glucuronide,
are unstable under these acid hydrolysis conditions and were not analyzed.
Figure 4. HPLC
analysis of urinary metabolites from rats given [2-14C]MeIQx
(37 mCi/mmole) at 0.01 mg/kg.
These metabolism pathways also occur in the rodent for the structurally
related food mutagen IQ after high dose exposure; however, the N2-glucuronide
conjugate of N-hydroxy-IQ was not detected (21,22). These
pathways also have been detected in nonhuman primates undergoing carcinogen
bioassays with MeIQx (23) and IQ (3,17). In the case of IQ,
several other metabolic routes were reported (17) including N-demethylation
and bacterial mediated oxidation at the C-7 position of the heterocyclic
nucleus.
We sought to determine whether humans detoxify MeIQx by phase II conjugation
reactions, such as sulfamation and N2-glucuronidation,
and thus, analyzed MeIQx in urine, both before and after acid hydrolysis,
from seven subjects who consumed fried beef or fish (Figure 5). The values
of MeIQx recovered within 12 hr ranged between 2 and 22 ng. Following acid
hydrolysis, the amounts of MeIQx in urine increased 4- to 10-fold in six
of the subjects, while there was little change in the amount of MeIQx in
the urine of one subject. The acid labile metabolites of two subjects were
purified by solid phase extraction with the aminopropyl cartridges, and
the N2-sulfamate and the N2-glucuronide
phase II conjugates accounted for essentially all of the acid labile material
recovered as MeIQx. This data was supported by isolating urinary fractions
by HPLC at retention times corresponding to the respective conjugates followed
by NICI-GC-MS analysis of MeIQx after acid hydrolysis (15). Further
work is being carried out to confirm directly the identity of the conjugates
by mass spectrometry.
Figure 5. MeIQx
content in human urine following consumption of pan-fried beef or fish.
Analyses were made before and after acid hydrolysis.
Discussion
To assess human exposure to HAAs, rapid and reliable analytical methods
are required to quantitate these compounds in foods. We demonstrated previously
that immunoaffinity chromatography rapidly isolates HAAs from complex mixtures
(24). However, due to the high selectivity of monoclonal antibodies,
analysis and quantification of HAAs are limited to the compound against
which the antibody is raised (and possibly several structurally related
compounds). Consequently, a broad panel of antibodies is required for immunoaffinity
purification of the many structurally diverse HAAs found in cooked foods.
Therefore, we developed a more general analytic method that could be used
to detect a wide range of HAAs. With this solid phase tandem extraction
procedure, it is possible to analyze simultaneously 11 HAAs formed in cooked
foods at the low parts per billion level by HPLC (13,14). We have
seen that grill scrapings, often used as a gravy base, may contain high
levels of HAAs. This is in agreement with high levels of mutagenicity reported
in gravy (25) and indications that the critical precursors of HAA
formation are present in the meat juice (26 ).
Protein dosimetry has been used to monitor human exposure to several
classes of carcinogens (10). The rodent model is a good surrogate
for blood protein adduct formation of several different carcinogens, including
the alylamine 4-aminobiphenyl, where over 5% of a dose binds to hemoglobin
via an acid labile sulÞnamide linkage. This adduct is also formed
in humans at comparable levels and results from a series of reactions between
the hemoprotein and the carcinogenic N-hydroxy metabolite (10).
However, the binding of MeIQx to hemoglobin in the rat is below 0.01% of
the dose and induction of cytochrome P450 actually resulted in lower levels
of protein binding (15). Blood protein binding of the HAA analog,
IQ, is also very low in rodents (27) and in nonhuman primates (17).
Hemoglobin sulfinamide adducts of IQ and MeIQx are formed in vitro
using enzymatically generated or synthetic N-hydroxy derivatives
(27) indicating that these genotoxic metabolites are sufficiently
stable to penetrate the erythrocyte and react with the hemoprotein. The
absence of this adduct in vivo suggests that very low levels of the
N-hydroxy metabolites are excreted by the liver into the blood stream.
Thus, based on animal models, human monitoring of these two mutagens by
protein dosimetry may be difficult. In support of this conclusion, a preliminary
study assaying for hemoglobin sulfinamide adducts of MeIQx in humans showed
that the adducts, if present, were below levels of detection using NICI-GC-MS
(28). An IQ sulfinamide-serum albumin adduct has been detected in
rodents (27) and this linkage may be formed for many aromatic and
heterocyclic aromatic amines as well (10). However, in the case of
IQ and MeIQx, the levels are low and protein dosimetry with such an adduct
may prove difficult.
MeIQx is rapidly absorbed and extensively metabolized in the rat to form
Þve principal metabolites which are excreted in urine. Four of these
metabolites are detoxification products, while the Þfth is a metastable
N2-glucuronide conjugate of the genotoxic metabolite N-hydroxy-MeIQx
(15). At the lowest dose of MeIQx administered (0.01 mg/kg), the
N2-sulfamate and N2-glucuronide excreted
in urine accounted for approximately 25% of the urinary excretion of MeIQx
and its metabolites (corresponding to approximately 5% of the total dose).
This dose is only several hundred-fold greater than daily human exposure
to MeIQx (1). Sulfamate formation and N2-glucuronidation
are two of the major routes of MeIQx and IQ detoxification. In rodent (15,19,21,22,29),
nonhuman primate (23) and human liver also appear to catalyze these
reactions in vitro [(30); R Turesky, unpublished observations].
In preliminary experiments with humans, six of seven subjects excreted
MeIQx metabolites as acid labile phase II conjugates, while there was no
evidence of acid labile metabolite formation in the remaining subject. The
4- to 10-fold increase in MeIQx content in human urine following acid hydrolysis
is comparable to the increase of MeIQx detected in urine of rodents given
MeIQx at 0.01mg/kg following acid treatment. We isolated these acid labile
metabolites from two human subjects, and nearly all of the acid labile material
recovered as MeIQx is attributed to the N2-sulfamate and
the N2-glucuronide conjugates. With the development of
internal standards for these metabolites, a better estimation of their relative
contribution to MeIQx metabolism and detoxification can be determined. Rodents,
nonhuman primates, and humans appear to have at least two common metabolic
routes of MeIQx detoxification.
Recently, the thermostable phenolsulfotransferase (TS PST) in human liver
was shown to catalyze the sulfamation of 2-naphthylamine (31). This
sulfotransferase also appears to be responsible for the metabolic activation
of several N-hydroxy aromatic and heterocyclic aromatic amines to
reactive DNA binding species (32,34). Thus, sulfotransferase has
a dual role in HAA metabolism and is involved both in metabolic activation
as well as detoxification. TS PST activity varies greatly in individuals
and exhibits a genetic poly- morphism (31,33). Consequently, studies
are required to assess the role of human sulfotransferases in HAA carcinogenesis.
Human liver metabolically activates MeIQx and other HAAs through cytochrome
P450-mediated N-oxidation and subsequent esterification reactions
to produce the ultimate carcinogenic metabolites (4-7,32,34). Analytic
developments are underway to quantify the N-hydroxy-N2-glucuronide
conjugate of MeIQx, an index of metabolic activation of this procarcinogen,
in human urine. This method will be used to evaluate better both the metabolic
activation and detoxification of MeIQx and, therefore, to assess health
risk of this dietary mutagen.
Note Added in Proof
We recently have identified a glucuronide conjugate of MeIQx in urine
and bile of nonhuman primates undergoing carcinogen bioassays (23).
1H-NMR and FAB-MS spectroscopy support the structure as a N1-glucuronide
(Turesky RJ, Welti DH, Fay LB, Snyderwine EG, unpublished observations).
The relative contribution of this metabolite, which has very similar chromatographic
properties to MeIQx-N2-glucuronide, in human detoxification
of MeIQx remains to be established.
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