[CANCER RESEARCH 39, 4579-4583,
0008-5472/79/0039-OOOOS02.00
November 1979]
Metabolism of Three Radiolabeled Pancreatic Carcinogenic Nitrosamines
in Hamsters and Rats1
Ralph Gingell,2 Galen Brunk, Donald Nagel, and Parviz Pour
Eppley Institute for Research in Cancer. University of Nebraska Medical Center, Omaha, Nebraska 68105
ABSTRACT
The in vivo metabolism and disposition of three radiolabeled
N-nitrosamines which are carcinogenic for the pancreas of the
hamster but not the rat have been examined. /V-[1-14C]Nitrosobis(2-oxopropyl)amine
(BOP), A/-[1-14C]nitrosobis(2-hydroxypropyDamine (BMP), and their suggested proximate pan
creatic carcinogenic metabolite A/-[1-14C]nitroso-(2-hydroxypropyl)(2-oxopropyl)amine
(HPOP) were metabolized and ex
haled as 14CO2 to various extents somewhat proportional to
their carcinogenic potency. More than 50% of the dose of BOP
and HPOP was exhaled as 14CO2, whereas 26% of BMP was
excreted this way, and 40% of BMP was excreted unchanged
in the urine. Administered BOP was excreted to a small extent
in the urine of both species as HPOP and BHP. No other
nitrosamine metabolites were detected in urine. HPOP and
BHP were detected in the pancreatic juice and bile of both
species after administration of BOP and BHP. The results
suggest that pancreatic ductular carcinogenesis in the hamster
as a result of exposure to BOP is not due to secretion of
carcinogenic metabolites in the pancreatic juice or reflux of
bile containing nitrosamine metabolites into the ducts. Carcin
ogen metabolic activation appears to be by an oxidative path
way.
INTRODUCTION
When Syrian golden
hamsters
were given BHP3 by s.c.
injection once weekly for life, a high incidence of pancreatic
ductular cell tumors was induced, as well as lung, liver, and
kidney tumors (16). However, when rats were similarly treated
with BHP, tumors occurred in the nasal cavity, lungs, esopha
gus, liver, and kidneys but not in the pancreas (9, 19). Com
pared to BHP, BOP was more toxic and induced more pan
creatic ductular tumors, fewer liver and kidney tumors, and no
lung tumors in hamsters (14). In the rat, the main target organs
of BOP were the intestines, liver, and respiratory and urogenital
tracts but not the pancreas (13). A/-Nitroso-2,6-dimethylmorpholine was also a pancreatic carcinogen in the hamster (6)
but not in the rat (8). BOP, BHP, and A/-nitroso-2,6-dimethylmorpholine were metabolized in the hamster to HPOP, which
can exist in open and cyclic forms, and HPOP has been
suggested to be responsible for the pancreatic carcinogenicity
of these compounds (3, 4). The metabolic interrelationship of
these compounds with the cyclic form of HPOP is illustrated in
1 Supported
by USPHS Contract
NO1 CP33278
from the National Cancer
Institute, NIH, and Grant NO1 R26 CA20198-01.
2 To whom requests for reprints should be addressed.
3 The abbreviations used are: BHP, W-nitrosobis(2-hydroxypropyl)amine;
BOP,
N-nitrosobis(2-oxopropyl)amine;
HPOP. N-nitroso(2-hydroxypropylX2-oxopropyUamine; DMN, W-nitrosodimethylamine;
TLC, thin-layer chromatography;
HPLC, high-pressure liquid chromatography.
Received January 8, 1979; accepted August 14. 1979.
Chart 1. HPOP itself has a carcinogenic potency similar to that
of BOP, further suggesting that it may be the proximate pan
creatic carcinogenic metabolite in hamsters (17). The in vivo
metabolism and disposition of BOP and BHP in the rat and
hamster, especially with respect to HPOP formation, has been
examined in an attempt to account for the species differences
in organotropism of these compounds and to differentiate
between proposed mechanisms of pancreatic carcinogenesis.
In preliminary studies, only a relatively small percentage of the
administered dose of BOP or BHP could be recovered in
hamster urine (4). Consequently, the 14C-labeled compounds
were synthesized to perform more detailed studies.
MATERIALS
AND METHODS
Chemicals. [1-'4C]BHP (0.238 ¿iCi/mg)was synthesized (5)
and was >97.5% pure by autoradiography after TLC (Table 1).
Most of the radioactive impurity remained at the origin, but
0.5% was present as HPOP. [1-14C]BOP (0.19 juCi/mg) was
prepared by chromic acid oxidation of [1-14C]-diisopropanolamine followed by nitrosation (10). This was purified by
preparative layer chromatography to >96% purity, the major
impurity remaining at the origin. [1-14C]HPOP (specific activity,
0.19 juCi/mg) was a by-product in the preparation of [14C]BOP
and was purified to >97% as above. These compounds were
stored frozen as aqueous solutions at —20°and did not de
compose appreciably under these conditions, as determined
by TLC followed by autoradiography.
Metabolism in Vivo. Male Syrian hamsters, 8 to 10 weeks
old, weighing 100 to 120 g, or 9- to 10-week-old male Wistarderived rats weighing about 200 g, received i.p. injections of
[14C]BHP, [14C]BOP, or [14C]HPOP (10 or 100 mg/kg). These
doses were similar to those in the carcinogenicity studies and
were based on toxicity, as determined by the 50% lethal dose
(14, 16). The animals were maintained in sealed glass metab
olism cages (Crown Scientific, Riverdale, III.) without food, but
with water ad libitum. Any volatile metabolites were trapped by
first bubbling expired air through 0.1 N HCI or a dry ¡cerethanol
trap. 14CO2 was trapped by bubbling through a solution of
ethanolamine:methanol (1:1), and was measured at 1, 3, 6, 12
and 24 hr by scintillation counting in Aquasol (New England
Nuclear, Boston, Mass.) using a Beckman LS-335 liquid scin
tillation system (Beckman Instruments,
Fullerton, Calif.).
Twenty-four-hr urine was collected 'separately from feces and
frozen over dry ice. Aliquots of urine were counted in Aquasol
after decolorization with several drops of 30% aqueous hydro
gen peroxide.
Modification of Metabolism. The effect of several known
modifiers of nitrosamine metabolism on CO2 production from
[14C]BOP and [14C]BHP was examined. Hamsters were main
tained for 1 week on drinking water containing
sodium phe-
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4579
R. Gingell et al.
CH,
CH,
C=0
-OH
CH,
CH,
V
NO
BOP
HPOP
CH,
CH,
HO-CH
l
CH,
HC-OH
l
CH,
cyclic
HPOP
CH,
CH,
1
CH
l
CH,
CH
l
CH,
RESULTS
BHP Metabolism. When hamsters were given i.p. injections
of [14C]BHP (100 mg/kg), approximately 74% of the radioac
tivity was excreted in the urine and 19% was excreted as CO2
in 24 hr (Chart 2; Table 2). HPLC of méthylène
chloride extracts
of urine revealed only HPOP and unchanged BHP as urinary
metabolites (Chart 3A). TLC of ethanol-precipitated
urine on
silica gel developed in Solvent 2 and followed by autoradiography revealed that 41 % of the administered BHP was excreted
unchanged, 1% as HPOP, and an unknown metabolite ac
counted for 8%. The remainder of the excreted dose (about
20%) stayed at the origin. The urine from hamsters given an
equivalent dose of [14C]bicarbonate also contained this un
Chart 1. In vivo metabolic interrelationship of BOP and related pancreatic
carcinogenic nitrosamines. All steps are metabolic except a, which is a chemical
tautomerization. NDMM, N-nitroso-2,6-dimethylmorpholine.
known metabolite, suggesting that it was due to 1-carbon-pool
intermediary metabolism. Urea has a similar RF in this solvent,
but when the urine was treated with urease (Sigma, St. Louis,
Mo.) before preparation for chromatography, the band did not
disappear. We were unable to modify TLC profiles by treatment
of urine for 1 hr with 1 N HCI, 1 N NaOH, or 5000 units of /?glucuronidase at 37°,indicating that no conjugates were pres
nobarbital
ent.
Rats given the same dose of [14C]BHP excreted 73% in the
NO
N
l
NO
BHP
NDMM
l
(1 mg/ml)
prior to [14C]BHP treatment.
Pyrazole
(200 mg/kg) or /V,A/-diethylformamide (20 mg/kg) in water
were injected i.p. 2 hr prior to [14C]BOP administration. Disulfiram (1000 mg/kg), as a suspension in aqueous corn starch,
was administered p.o. 2 hr prior to [14C]BOP. Ethanol (2 ml/
kg) or disulfiram (500 mg/kg suspended in aqueous
starch) was administered p.o. 0.5 hr prior to [14C]BOP.
corn
Collection of Bile and Pancreatic Juice. Bile and pancreatic
juice were collected from hamsters (2) and rats after i.p.
administration of [14C]BOP. For pancreatic juice and bile col
urine and 4% of the dose as CO2. The rate of BHP metabolism
to CO2 (Chart 2) was less in the rat than in the hamster. Profiles
of rat urine metabolites, however, showed no significant differ
ences from those of hamster urine.
BOP Metabolism. The quantitative recovery of radioactivity
after administration of BOP (10 mg/kg) to hamsters and rats is
given in Table 2, and the rates of metabolism to expired CO?
are given in Chart 2. Hamsters given [14C]BOP excreted 12%
of the dose in the urine and expired 67% as CO2. TLC of
lection from rats, the common duct was ligated at the junction
hamster urine on silica gel plates developed in Solvent 3,
with the duodenum and about 0.5 inch distally. The duct was followed by autoradiography, yielded a Chromatographie profile
cannulated with PE50 tubing near the junction with the duo
denum for pancreatic juice and above the second ligature for
Table 1
bile collection. Animals were kept in plastic restraining cages
Chromatography of nitrosamine
(Fisher Scientific, Fair Lawn, N. J.) when conscious, and when
RF x 100/retention time (min)
unconscious body temperature was maintained at 37 ± 2°
with a heating pad. Aliquots of bile were counted, after decolorization, in Aquasol.
Identification of Metabolites. Radioactive metabolites were
recovered for chromatography from urine, bile, and pancreatic
juice by adding 10 volumes of absolute ethanol and leaving the
liquids to stand overnight at —20°to allow precipitation of
debris. After filtration, the extracts were concentrated by rotary
evaporation at 40°, and the above process was repeated, if
necessary, prior to concentration to a small volume under a N2
stream for TLC. Silica TLC plates were developed in compari
son with authentic standards (Table 1). Autoradiography was
performed by exposing TLC plates to Kodak SB54 X-ray film.
Metabolites were quantitated by scraping from the TLC plates
and adding 1 ml methanol, followed by scintillation counting as
before. In other experiments, urine from treated animals was
extracted with 3x5
volumes méthylènechloride and evapo
rated to a small volume under a stream of N2, and metabolites
were identified by HPLC as detailed in Table 1. Fractions were
collected into vials as they eluted from the HPLC detector, and
radioactivity was determined by scintillation counting. Metab
olite identification was confirmed by gas-liquid chromatography
(Table 1).
4580
CompoundBOP
1a55
245
chroma
tography06.9
398
42, 55tf
30, 35Ö
HPOP
10.9
94
7.69.4
BHPSystem
23TLCSystem 23System 83HPLC66.623.8Gas-liquid
" System 1: 250-/im-thick silica gel plates with fluorescent indicator (Analtech). Solvent: méthylènechlorideiethyl acetate (1:1, v/v). System 2: As for
System 1. solvent: méthylènechloride:ethyl acetate (4:1. v/v). System 3: As for
System 1. Méthylènechloride:methanol (3:1). Compounds were located under
UV illumination and by autoradiography.
6 HPLC was performed using a Waters 6000A solvent delivery system and a
Waters U6K injector and with detection at 240 nm using an L. D. C. Spectromonitor II UV detector. A Lichrosorb Si 60 column (3.2 mm x 25 cm. 5-fjrn
particle size) with a Corasil II precolumn was used for separation. Compounds
were eluted with a 5-min gradient at an initial concentration of 0.5% ethanol in
méthylènechloride to a final ethanol concentration of 2%, using Program 4 of
the Waters programmer. Solvent flow rate was 1 ml/min at a pressure of 1100
psi. Amounts of nitrosamines were calculated using a Hewlett-Packard 3380A
recording integrator. The values reported are corrected for recovery of known
amounts of authentic standards under these conditions.
'' GC was performed using a Hewlett-Packard
5730A gas Chromatograph
equipped with a 2-mm x 6-foot glass column packed with 5% SP2100 (Supelco)
on 100 to 200 mesh Supelcoport, and flame ionization detection. The column
oven was programmed from 80°to 140°with temperature raised at 4°/min. and
Nj carrier gas flow rate was 20 ml/min.
" These 2 values represent the cyclic (greater)
and open forms of HPOP
which are separated in these systems.
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39
Metabolism of Pancreatic Carcinogenic
with more than 10 distinct radioactive bands. Three metabolites
have been identified as BOP, HPOP and BHP. One band
matched the RF of the band derived from bicarbonate metab
olism, as for BHP, and is also probably due to 1-carbon-pool
intermediates. Less than 1% of the dose was recovered in the
feces; this may have been due to contamination with urine.
Using the Preussmann spray reagent (18) under conditions
which show BHP and HPOP as positive, no other bands gave
a positive response, indicating that they are probably not
nitrosamines. No other nitrosamine metabolites were detected
by HPLC (Chart 3B).
Rats given [14C]BOP i.p. at 10 mg/kg excreted 23% of the
dose in urine and expired 55% as CO2 (Table 2; Chart 2). Less
than 1% was recovered in the feces. TLC profiles of the rat
urine appeared quantitatively similar to those of the hamster;
differences were only in the relative amounts of some of the
bands.
HPOP Metabolism. The small quantity of [14C]HPOP availa
Nitrosamines
Table 2
In vivo metabolism of["C]nitrosamines
metabolite
excretedSpeciesHamsterRatCompound'14C-BOPMC-HPOP"C-BHP1
% of dose
dose)BOPTr*000HPOP4832BHP53391
(% of
urine12
757 ±
±626
455 ±
-C-BOPasCO267
±7in
224 ±
±266
623 ±
±8Urinary
Each compound was administered i.p. at 10 mg/kg, and urine and expired
CO2 were collected for 24 hr. No compound was detected in expired air. Results
are the mean ±S.D. for at least 3 animals. Amounts of specific metabolites are
taken from pooled urines of 3 animals.
b Tr, trace.
period. In the bile, hamsters secreted 1.6% and rats secreted
4.4% in 24 hr. Most of the 14Cin bile and pancreatic juice was
removed from solution by the ethanol precipitation method or
stayed at the origin on TLC, implying that it was mostly present
ble permitted only limited metabolic studies. HPOP was rapidly
in
bile acids and proteins as a result of 1-carbon pool incor
and extensively metabolized to CO2 in the hamster (Chart 2;
Table 2) and excreted to a small extent unchanged and as BHP poration. Of the administered dose to rats, 0.2% was ac
counted for as HPOP and 0.05% as BHP in the bile, and 0.1
in the urine. Chromatographie profiles of urine extracts were
and 0.02%, respectively, in the pancreatic juice. Similar trace
similar to those obtained for BOP, except no BOP was de
amounts of HPOP and BHP were also detected in hamster
tected.
Inhibition of Metabolism. None of the pretreatments with pancreatic juice and bile.
phénobarbital, pyrazole, disulfiram ethanol, or diethylformamide had any significant effect on rates of CO2 production from DISCUSSION
[14C]BOP or [14C]BHP.
The synthesis of 3 14C-labeled nitrosamines has allowed
Biliary and Pancreatic Secretions. The amounts of 14C
secreted in the bile and pancreatic juice of hamsters and rats
that received 10-mg/kg i.p. injections of [14C]BOP are given in
more detailed metabolic studies of these pancreatic ductular
carcinogens. Previously, when only solvent extraction and gas-
Table 3. Hamsters secreted 0.36% and rats secreted 0.67%
of the radioactive dose in the pancreatic juice over a 24-hr
liquid chromatography were used for detection, less than 25%
of the administered 100-mg/kg dose of BHP and HPOP and
less than 10% of the same dose of BOP were recovered as
BHP and HPOP in the urrne (4). Using 14C-labeled compounds,
metabolism studies have been possible at the 10-mg/kg car
I2
TIME
24
(hr)
Chart 2. Metabolism of ["CJnltrosamines to "CO2. The extent of metabolism
of ["C]BOP. [14C]HPOP, and ["CIBHP to ^CO, was determined at various times
after i.p. administration. The 24-hr cumulative dose is the mean ±S.D. (bars) for
at least 3 animals. O, BOP (10 mg/kg) to hamster; *, HPOP (10 mg/kg) to
hamster; •BOP (10 mg/kg) to rat; •BOP (100 mg/kg) to hamster; A. BHP (10
mg/kg) to hamster; D, BHP (100 mg/kg) to hamster; A, BHP (100 mg/kg) to
rat.
cinogenic dose of BOP and HPOP.
HPOP has been proposed to be the pancreatic carcinogenic
metabolite of BOP and BHP in hamsters, since it is a common
metabolite of both (4). HPOP has a carcinogenic potency, with
respect to the hamster pancreas, similar to that of BOP (17).
The rat, which does not develop pancreatic tumors, also is able
to metabolize BOP to HPOP. Thus, this resistance of the rat is
not due to a species difference in metabolic activity.
The hamster pancreatic ductular cells may be exposed to
these carcinogenic
nitrosamines, and thus induce tumors,
either systemically by secretion in the pancreatic juice or by
biliary reflux into the pancreatic duct, a postulated mechanism
for human disease (23). Species differences in the nature of
metabolites in bile or pancreatic juice might be expected be
tween the rat and hamster if one of the latter 2 mechanisms is
important in pancreatic carcinogenesis.
However, trace amounts of HPOP and BHP were detected in
bile and pancreatic juice of both species treated with [14C]BOP,
and no major differences could be attributed to pancreatic
carcinogenesis. Thus, neither reflux of bile containing carci
nogenic metabolites into the pancreatic duct nor direct secre
tion in the pancreatic juice is likely to be a mechanism of
pancreatic ductular carcinogenesis in this animal model, which
is probably due to systemic exposure to the metabolite HPOP.
This result has been previously suggested by carcinogenesis
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4581
R. Gingell et al.
1000
40
FRACTION
50
160
NUMBER
90
100
BMP
5/00
FRACTION
NUMBER
BMP
Chart 3. Urinary metabolites of BOP and BMP in hamsters. Representative HPLC profiles of urine extracts of hamsters after i.p. administration of M) [14C]BHP or
(B)["'C]BOP(10mg/kg).
bioassays of BOP in surgically pretreated hamsters (15). No
other nitrosamine metabolites that could be related to pan
creatic carcinogenesis were detected in urine, pancreatic juice,
or bile.
BOP induced colorectal tumors in rats (13), but secretion of
BOP metabolites in bile does not seem to be the mechanism of
their induction, since the rate and nature of biliary metabolite
secretion was similar in rats and hamsters. Only trace amounts
of 14Cwere detected in the feces of rats given BOP, indicating
that colorectal tumors are also probably due to systemic ni
trosamine exposure.
The major finding of these studies using 14C-labeled nitros-
4582
amines was that much of the administered dose was metabo
lized to exhaled CO2. BOP and HPOP, the more toxic and
potent carcinogens, were extensively metabolized to CO2, and
the less toxic and weaker carcinogen BMP was less readily
metabolized to CO2. This was true at both the 10 mg/kg and
100 mg/kg doses although, as noted by Snyder ef al. (21 ), the
extent of metabolism to CO2 for each compound was dose
dependent. The effect of various reported modifiers of nitros
amine metabolism on BMP and BOP disposition was investi
gated in an attempt to identify potential modifiers of carcino
genesis. Pyrazole had been reported to decrease the metabo
lism of DMN to CO2 in rats and also protect the liver from the
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Metabolism of Pancreatic Carcinogenic
Table 3
Secretion of "C in the pancreatic juice and bile after l"C]BOP
Bile and pancreatic juice were collected from hamsters and rats after admin
istration of ['"C1BOP (10 mg/kg ¡.p.).
CompoundPancreatic
(hr)0-6
dose0.32
of
±0.05a
6-240-6
0.13
0.020.48
±
6-240-6
±0.33
0.19
0.021.29
±
6-240-6
±0.20
0.31
0.043.68
±
6-24%
±2.10
0.72 ±0.12
juiceBileSpeciesHamsterRatHamsterRatTime
3.
4.
5.
6.
7.
a Mean ±S.D. for 3 animals.
toxic effects of DMN administration, due to a direct effect on
DMN demethylase (11, 12). Diethylformamide was also re
ported to inhibit protein methylation and DMN metabolism to
CO2 in vivo (7). Disulfiram treatment markedly decreased the
hepatocarcinogenicity
of DMN in rats (20), presumably by
inhibiting hepatic metabolism (22). However, in our studies, no
significant decrease in the rate of metabolism of BOP or BHP
was detected with these inhibitors. Possibly, these reported
inhibitors of oxidative metabolism and toxicity of simple dialkyl
nitrosamines have no effect on BOP and BHP metabolism
because these are already partially oxidized.
/V-Nitrosamines are currently thought to be metabolically
activated to carcinogens by a-oxidation ultimately to give carbonium ions which react with DNA to initiate tumors (1). Other
decomposition products of a-oxidized nitrosamines are alde
hydes and alcohols, which may be metabolized in vivo via 1carbon pool intermediates to CO2. All 3 nitrosamines studied
are labeled in the carbon atom a to the nitroso group. The fact
that the rate of metabolism of these compounds to CO2 corre
lated somewhat with their relative toxicity and carcinogenic
potency suggests that a-oxidation is also a mechanism of their
activation. This possibility is being examined in various target
and nontarget organs using in vitro techniques.
ACKNOWLEDGMENTS
The authors are grateful to R. Kupper, J. Meehan, and Katla Donnelly for
technical assistance and to Mardelle Susman for editorial advice.
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4583
Metabolism of Three Radiolabeled Pancreatic Carcinogenic
Nitrosamines in Hamsters and Rats
Ralph Gingell, Galen Brunk, Donald Nagel, et al.
Cancer Res 1979;39:4579-4583.
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