A comparative study of hepatic and colonic metabolic enzymes in inbred mouse lines before and after treatment with the colon carcinogen, 1,2-dimethylhydrazine.
1,2-Dimethylhydrazine (DMH) is an organotropic colon carcinogen that undergoes metabolic activation to DNA-reactive metabolites. Twenty hours after parenteral treatment of AKR/J (colon tumor resistant) and SWR/J (susceptible) mice with DMH.2HCl (70 mg/kg), functional levels of Cyp1a1 and Cyp2e1 were examined by measuring O-deethylation of ethoxyresorufin (EROD) and hydroxylation of p-nitrophenol, respectively. In control animals, SWR/J mice exhibited higher hepatic EROD activity (1.4-fold) when compared with AKR/J mice. In carcinogen-treated animals, EROD activity was decreased 20-30% in both mouse lines. Hepatic p-nitrophenol hydroxylase activity, similar in control animals of both strains, was reduced comparably (45-50% of control) after DMH administration. In liver, a decrease in immunoreactive Cyp2e1 protein paralleled the decline in enzyme activity, whereas in the colon, no significant treatment-related differences were detected in either strain. In liver and colon cytosols, alcohol dehydrogenase activity was not significantly different in either mouse line, both in control and DMH-treated animals. Glutathione levels were elevated (1.7-fold) in livers of AKR/J mice after DMH administration. Total glutathione-S-transferase (GST) activity was significantly increased (1.8-fold) in the colons of SWR/J mice and in the livers (1.4-fold) of AKR/J mice. Furthermore, the GST isoform, GST-Yp, was reduced 40% in the SWR/J colon. These data demonstrate the importance of metabolic capacity as a factor in conferring differential tumor susceptibility in a murine cancer model to the indirect-acting colon carcinogen, DMH.
Delker
D A
DA
Department of Pharmaceutical Sciences, University of Connecticut, Storrs 06268, USA.
Bammler
T K
TK
Rosenberg
D W
DW
D019813:1,2-Dimethylhydrazine; D000426:Alcohol Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000008:administration & dosage*; D003106:Colon / Q000187:drug effects* / Q000201:enzymology; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004127:Dimethylhydrazines / Q000008:administration & dosage*; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D010641:Phenotype
D002273:Carcinogens; D004127:Dimethylhydrazines; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D005982:Glutathione Transferase; D019813:1,2-Dimethylhydrazine