* Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky 40292; and
Department of Pharmacology and Toxicology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202
Received July 17, 2000; accepted October 16, 2000
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ABSTRACT |
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Key Words: N-acetyltransferase 2 (NAT2); 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, PhIP; acetylator genotype; DNA adducts; Syrian hamster.
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INTRODUCTION |
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PhIP must undergo host-mediated biotransformation to genotoxic species in order to exert mutagenic and carcinogenic effects (Alexander et al., 1994; Buonarati et al., 1990
; Kaderlik et al., 1994a
). Following N-hydroxylation, N-acetyltransferases catalyze the O-acetylation of N-hydroxy-PhIP to N-acetoxy-PhIP (Buonarati et al., 1990
; Hein et al., 1994b
; Minchin et al., 1992
). N-acetoxy-PhIP is unstable and spontaneously hydrolyzes to an arylnitrenium ion that binds DNA. PhIP does not undergo N-acetylation (deactivation) in vitro, unlike many aromatic amine carcinogens (Hein et al., 1993
), but phenotypic differences in O-acetylation of N-hydroxy-PhIP may lead to differences in DNA adduct formation. PhIP binds to the C-8 position of guanine nucleotides forming N-(deoxyguanosin-8-yl)-PhIP (Lin et al., 1992
). The formation of DNA adducts may induce mutations in proto-oncogenes and tumor suppressor genes leading to the formation of neoplastic lesions. Thus, genetic differences in O-acetyltransferase phenotype may result in differential cancer susceptibility following exposure to heterocyclic amine carcinogens such as PhIP.
A genetic acetylation polymorphism exists in humans (Hein et al., 2000) and Syrian hamster (Hein et al., 1997
). Slow acetylator congenic Syrian hamsters are homozygous for the NAT2*16A allele containing a premature stop codon (Ferguson et al., 1994a
) which encodes a deficient NAT2 enzyme (Ferguson et al., 1996
). Rapid and slow acetylator Syrian hamsters differ in N- and O-acetyltransferase activity (Hein et al., 1994), and in levels of hemoglobin-adduct (Feng et al., 1994
), DNA-adduct (Feng et al., 1996b
) and aberrant crypt foci (Feng et al., 1996c
; Paulsen et al., 1996
) induced by aromatic amine carcinogens. Phenotypic differences in O-acetyltransferase catalyzed by NAT2 may lead to differences in bioactivation of heterocyclic amines, DNA adduct formation, and tumor incidence.
As recently reviewed, numerous human epidemiological studies have investigated the role of acetylator genotype in cancer susceptibility (Hein et al., 2000). Some studies suggest a role for the NAT2 rapid acetylator genotype and cancer incidence, but not all investigations support this relationship. Epidemiological studies often are limited in their power to study the role of the metabolizing enzymes in cancer susceptibility because of numerous factors including lack of a homogeneous population, insufficient exposure data, and other confounding factors.
The congenic hamster model provides a useful model to investigate the relationship between acetylator genotype and heterocyclic amine carcinogenesis. The construction and characterization of the rapid- and slow-acetylator congenic hamster model has been described (Hein, 1991; Hein et al., 1994a
). Rapid and slow acetylator congenic hamsters are theoretically 99.975% genetically identical differing only at the NAT2 locus (Ferguson et al., 1994a
, 1996
) or other tightly linked loci. This virtually eliminates genetic polymorphism in other metabolism, DNA repair, and oncogenesis pathways facilitating investigation into the specific role of the acetylation polymorphism in tumorigenesis. Urinary bladder and colon tumors are induced in the Syrian hamster by 3,2-dimethyl-4-aminobiphenyl (Feng et al., 1999
; So and Winder, 1972; Williams et al., 1981
), an aromatic amine carcinogen related to PhIP. Thus, we utilized Syrian hamsters, congenic at the NAT2 locus, to investigate the specific role of the acetylation polymorphism in PhIP-induced carcinogenesis.
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MATERIALS AND METHODS |
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PhIP-DNA adducts.
PhIP was dissolved in a solution of 0.1 M HCl/dimethylsulfoxide (3:2, v/v) at a concentration of 10 mg/ml. Twelve-week old rapid (n = 4) and slow (n = 4) acetylator congenic hamsters were administered 4 daily doses of 100 mg/kg body weight PhIP by oral gavage. One rapid- and one slow-acetylator congenic hamster received vehicle alone as a control. Control and treated hamsters were sacrificed 6 h after the last dose, and tissues were collected, snap frozen in liquid nitrogen, and stored at 80°C until the PhIP-DNA adduct levels were measured.
Analysis of PhIP-DNA adducts.
PhIP-DNA adduct levels were measured by the 32P-postlabelling method, as previously described (Leff et al., 1999). Briefly, genomic DNA was isolated by digestion with proteinase K, followed by phenol:chloroform extraction. PhIP-DNA adducts were resolved by thin-layer chromatography, quantified using the Instant Imager electronic autoradiography system (Packard Instruments, Chicago, IL), and compared with synthetic PhIP-DNA-adduct standard, N-(deoxyguanosin-8-yl)-PhIP.
PhIP bioassay.
Twelve-week-old rapid- (n = 23) and slow- (n = 23) acetylator congenic male hamsters were administered 11 doses of PhIP (75 mg/kg) by oral gavage. The dosing regimen consisted of 2 doses per week for 4 weeks, followed by a single dose per week for 1 week and finally, 1 dose every other week for the final 2 doses. Three rapid- and 3 slow-acetylator congenic hamsters received vehicle alone as control. At the conclusion of dosing, all hamsters were placed on a polyunsaturated high-fat diet consisting of 23.5% corn oil. The PhIP dosing regimen followed by the high-fat diet is a slight modification from a PhIP dosing regimen (10 oral doses of 75 mg/kg PhIP over a 2-week period) that yields tumors in the female rat (Ghoshal et al., 1994; Snyderwine et al., 1998
). All hamsters were monitored daily for morbidity and mortality. Hamsters were sacrificed fifty-six weeks after the final dose, and all tissues were examined for gross abnormalities. In addition, each prostate and pancreas was fixed in 10% buffered formalin for 24 h, followed by storage in 70% ethanol. Tissues were embedded in paraffin and sectioned serially. The tissue sections were stained with hematoxylin-eosin-saffron and scored blind by a veterinary pathologist.
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RESULTS |
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DISCUSSION |
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No statistically significant differences in PhIP-DNA adduct levels were observed between rapid and slow acetylator congenic hamsters administered PhIP. This result is similar to the finding that rapid and slow acetylator congenic hamsters showed no differences in DNA adduct formation when administered 3,2`-dimethyl-4-aminobiphenyl (Feng et al., 1996a). Recent studies show that N-hydroxy-PhIP is activated to a much greater extent by recombinant Syrian hamster N-acetyltransferase 1 than recombinant Syrian hamster NAT2 (manuscript in preparation). Since rapid- and slow-acetylator congenic hamsters do not have a functional difference in N-acetyltransferase 1 phenotype (Ferguson et al., 1994b
), this could account for the lack of difference in DNA adduct levels between rapid- and slow-acetylator hamsters that might have been observed following administration of other doses of PhIP. However, in preliminary studies with lower doses, PhIP-DNA adduct levels were very low to non-detectable in most major organs of the hamster. Recent studies show that human sulfotransferase is very important in the metabolic activation of N-hydroxy-PhIP (Chou et al., 1995
; Wu et al., 2000
). Rapid and slow acetylator congenic hamsters do not differ in N-hydroxy-PhIP O-sulfotransferase activity (Fretland et al., in press), which may explain the lack of a difference in PhIP DNA adduct formation in rapid- and slow-acetylator congenic hamsters.
No tumors were observed in male rapid- and slow-acetylator congenic Syrian hamsters following oral administration of PhIP and maintenance on a high-fat diet for a year. The absence of prostate tumors following administration of PhIP to Syrian hamsters differs from the rat, in which PhIP induces prostate tumors (Shirai et al., 1997, 1999
). However, the PhIP-dosing regimen used in the rat studies (400 ppm in the diet for 52 weeks) differs substantially from the present hamster study (11 oral doses of 75 mg/kg). It is possible that alternative PhIP dosing regimens would induce prostate tumors in the hamster. The regimen used in the current study is a slight modification of the one that induces tumors in the female rat (Ghoshal et al., 1994
; Snyderwine et al., 1998
). We recently reported lack of aberrant crypt foci and tumors in the gastrointestinal tract of male and female congenic hamsters administered PhIP (Steffensen et al., 2000
). These results suggest that the male Syrian hamster is relatively resistant to PhIP tumorigenesis despite the widespread formation of PhIP-DNA adducts in target tissues. Absence of PhIP-induced tumors also was observed recently in the female hamster (Fretland et al., in press). In contrast, levels of DNA adducts (Purewal et al., 2000a
) and aberrant crypt foci (Purewal et al., 2000b
) were higher in rapid than slow acetylator inbred rats administered PhIP. Since human exposures to PhIP are much lower but for a much longer period of time than carried out in the present study, further studies are necessary to understand the role of the NAT2 acetylation polymorphism on DNA-adduct formation and susceptibility to PhIP-induced cancers in humans.
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ACKNOWLEDGMENTS |
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NOTES |
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2 Present address: Hoffmann La-Roche Pharmaceuticals, 340 Kingsland Street, Nutley, NJ 071101199.
3 To whom correspondence should be addressed. Fax: (502) 852-7868. E-mail: d.hein{at}louisville.edu.
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