Title

Metabolic and morphological analyses of colon tumor susceptibility: A strain and species-related comparison

Date of Completion

January 1997

Keywords

Health Sciences, Toxicology

Degree

Ph.D.

Abstract

A tumor susceptibility phenotype to the organotropic colon carcinogen 1,2-dimethylhydrazine (DMH) has been defined in inbred mice. DMH is an indirect-acting procarcinogen requiring metabolic activation. In the following studies, we examine the hypothesis that differential responsiveness to DMH, and its direct metabolite, azoxymethane (AOM), depend on the relative levels of a panel of metabolic enzymes that account for DMH activation. Among the enzymes examined, cytochrome P450 2e1 (Cyp2e1) and alcohol dehydrogenase (Adh) levels were similar in the livers and colons of both tumor susceptible (SWR/J) and resistant (AKR/J) mice. Glutathione S-transferase (GST) activity, important in the detoxification of electrophiles generated by carcinogen metabolism, was significantly increased (1.8-fold) in the colons of SWR mice and in the livers (1.4-fold) of AKR mice following DMH treatment. In contrast, GST-Yp, a highly expressed GST isoform in mouse colon, was reduced by 40% in the SWR colon as measured by immunoreactive protein. To directly test the relative capacity of liver and colon Adh to activate the proximate mutagenic metabolite of DMH, mouse cytosols were incubated with methylazoxymethanol (MAM). Neither AKR nor SWR cytosols metabolized MAM, although under identical assay conditions rat cytosols effectively metabolized MAM as previously reported. Finally, the possibility was examined that tumor multiplicity is dependent on the pool size of precancerous cells within the colonic epithelium. In addition to SWR and AKR, tumor susceptible strain A mice were repetitively administered AOM and examined for aberrant crypt foci (ACF), a precancerous lesion that can be visualized directly in methylene blue-stained whole colon mounts. SWR and strain A mice had a higher frequency of ACF (15 and 32 per cm colon, respectively) than AKR (5 per cm). In addition, a significant percentage (20 and 35%) of ACF were classified as large $({\ge}5$ crypts per foci) in the sensitive strains, compared with less than 4% in AKR. Taken together, these findings suggest that tumor resistant AKR mice are able to activate procarcinogens like AOM, and that factors that govern resistance to AOM, affect either the rate of ACF formation or the regression of these lesions within the colonic epithelium. ^