Initial levels of azoxymethane-induced DNA methyl adducts are not predictive of tumor susceptibility in inbred mice.

2.50
Hdl Handle:
http://hdl.handle.net/10541/93096
Title:
Initial levels of azoxymethane-induced DNA methyl adducts are not predictive of tumor susceptibility in inbred mice.
Authors:
Papanikolaou, A; Shank, R C; Delker, D A; Povey, Andrew C; Cooper, Donald P; Rosenberg, D W
Abstract:
Inbred mice vary in susceptibility to colon carcinogens such as 1,2-dimethylhydrazine (DMH). Differential susceptibility may depend, in part, on formation of promutagenic DNA methyl adducts within target colonic mucosa. The present study was undertaken to evaluate the extent of DNA adduct formation in susceptible (SWR) and resistant (AKR) mice acutely exposed to the colon carcinogen azoxymethane (AOM), a direct metabolite of DMH. In the first experiment, 8-week-old SWR and AKR mice were treated i.p. with 20 mg/kg AOM and sacrificed 6 h later. DNA was isolated from distal colon and liver, and O6-methylguanine (O6-MeGua) adduct levels were assessed by immunoslot blot (ISB) analysis, using a monospecific antibody raised against O6-methyldeoxyguanosine. HPLC-fluorescence detection was also used to quantitate 06-MeGua and 7-methylguanine (7-MeGua), and to generate standard curves. At 6 h, both O6-MeGua and 7-MeGua were significantly higher (2- to 3-fold, p < 0.05) in AKR colon, while an opposite pattern was found in liver. In Experiment 2, mice were injected with AOM (20 mg/kg) and euthanized 12 and 48 h later. At 12 h, O6-MeGua levels were higher in colons (1.4-fold) of SWR mice. Forty-eight hours after treatment, however, adduct levels in colon were markedly (5-fold) reduced in SWR but were unchanged from 12 h in AKR. To further compare activation of AOM in both strains, colon microsomes were incubated with AOM and calf thymus DNA. Comparable levels of O6-MeGua were detected by ISB, demonstrating equivalent metabolic capacity in both SWR and AKR mice. These studies suggest that differential susceptibility to AOM-induced colon carcinogenesis is not based on initial target tissue DNA alkylation and unlikely to depend on differential metabolic capacity.
Affiliation:
Department of Pharmaceutical Sciences, University of Connecticut, Storrs 06269-2092, USA.
Citation:
Initial levels of azoxymethane-induced DNA methyl adducts are not predictive of tumor susceptibility in inbred mice. 1998, 150 (1):196-203 Toxicol. Appl. Pharmacol.
Journal:
Toxicology and Applied Pharmacology
Issue Date:
May-1998
URI:
http://hdl.handle.net/10541/93096
DOI:
10.1006/taap.1998.8393
PubMed ID:
9630469
Type:
Article
Language:
en
ISSN:
0041-008X
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorPapanikolaou, Aen
dc.contributor.authorShank, R Cen
dc.contributor.authorDelker, D Aen
dc.contributor.authorPovey, Andrew Cen
dc.contributor.authorCooper, Donald Pen
dc.contributor.authorRosenberg, D Wen
dc.date.accessioned2010-02-25T16:53:13Z-
dc.date.available2010-02-25T16:53:13Z-
dc.date.issued1998-05-
dc.identifier.citationInitial levels of azoxymethane-induced DNA methyl adducts are not predictive of tumor susceptibility in inbred mice. 1998, 150 (1):196-203 Toxicol. Appl. Pharmacol.en
dc.identifier.issn0041-008X-
dc.identifier.pmid9630469-
dc.identifier.doi10.1006/taap.1998.8393-
dc.identifier.urihttp://hdl.handle.net/10541/93096-
dc.description.abstractInbred mice vary in susceptibility to colon carcinogens such as 1,2-dimethylhydrazine (DMH). Differential susceptibility may depend, in part, on formation of promutagenic DNA methyl adducts within target colonic mucosa. The present study was undertaken to evaluate the extent of DNA adduct formation in susceptible (SWR) and resistant (AKR) mice acutely exposed to the colon carcinogen azoxymethane (AOM), a direct metabolite of DMH. In the first experiment, 8-week-old SWR and AKR mice were treated i.p. with 20 mg/kg AOM and sacrificed 6 h later. DNA was isolated from distal colon and liver, and O6-methylguanine (O6-MeGua) adduct levels were assessed by immunoslot blot (ISB) analysis, using a monospecific antibody raised against O6-methyldeoxyguanosine. HPLC-fluorescence detection was also used to quantitate 06-MeGua and 7-methylguanine (7-MeGua), and to generate standard curves. At 6 h, both O6-MeGua and 7-MeGua were significantly higher (2- to 3-fold, p < 0.05) in AKR colon, while an opposite pattern was found in liver. In Experiment 2, mice were injected with AOM (20 mg/kg) and euthanized 12 and 48 h later. At 12 h, O6-MeGua levels were higher in colons (1.4-fold) of SWR mice. Forty-eight hours after treatment, however, adduct levels in colon were markedly (5-fold) reduced in SWR but were unchanged from 12 h in AKR. To further compare activation of AOM in both strains, colon microsomes were incubated with AOM and calf thymus DNA. Comparable levels of O6-MeGua were detected by ISB, demonstrating equivalent metabolic capacity in both SWR and AKR mice. These studies suggest that differential susceptibility to AOM-induced colon carcinogenesis is not based on initial target tissue DNA alkylation and unlikely to depend on differential metabolic capacity.en
dc.language.isoenen
dc.subjectExperimental Canceren
dc.subject.meshAnimals-
dc.subject.meshAzoxymethane-
dc.subject.meshBiotransformation-
dc.subject.meshCarcinogens-
dc.subject.meshCattle-
dc.subject.meshChromatography, High Pressure Liquid-
dc.subject.meshDNA-
dc.subject.meshDNA Adducts-
dc.subject.meshGuanine-
dc.subject.meshImmunoblotting-
dc.subject.meshMale-
dc.subject.meshMethylnitrosourea-
dc.subject.meshMice-
dc.subject.meshMice, Inbred AKR-
dc.subject.meshMice, Inbred Strains-
dc.subject.meshNeoplasms, Experimental-
dc.subject.meshPredictive Value of Tests-
dc.titleInitial levels of azoxymethane-induced DNA methyl adducts are not predictive of tumor susceptibility in inbred mice.en
dc.typeArticleen
dc.contributor.departmentDepartment of Pharmaceutical Sciences, University of Connecticut, Storrs 06269-2092, USA.en
dc.identifier.journalToxicology and Applied Pharmacologyen

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