DNA alkylation by 1,2-dimethylhydrazine in the rat large intestine and liver: influence of diet and enzyme induction.
Male Wistar rats were fed a semi-purified diet (MID - minimal inducing diet) with or without addition of 50 ppm of beta-naphthoflavone (BNF) for 1 week. After 1 week the rats were dosed with 20 mg/kg of 1,2-dimethylhydrazine (DMH) subcutaneously and killed at various time intervals from the injection. Enzyme levels were determined in microsomal and cytosolic fractions prepared from the liver and the intestinal mucosa. Feeding of BNF for 1 week caused a 6.5-fold increase of 7-ethoxyresorufin (7-ERR) deethylase in the colon as compared to the controls, but did not alter glutathione (GSH) content nor glutathione-S-transferase (GSHST) activity. Hepatic cytochrome P-450 and 7-ERR deethylation were not significantly altered by feeding of BNF at this concentration, whereas GSH and GSHST were increased by a factor of 1.6 and 2, respectively. In the DMH-dosed rats, O6-methylguanine was formed to a greater extent in the BNF-treated colon than in the controls at 1, 12 and 24 h, whilst N7-methylguanine levels were essentially the same in the induced and uninduced rats. No significant difference was found in the degree of hepatic DNA alkylation at any time points. As shown by our results, the nature of the diet would appear to be able to modulate the rate of metabolic activation of DMH and its binding to DNA in the target organ.
Tacchi-Bedford
A M
AM
Department of Clinical Pharmacology, University College London, U.K.
Whyman
G D
GD
McLean
A E
AE
D019813:1,2-Dimethylhydrazine; D000284:Administration, Oral; D000478:Alkylation; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D003106:Colon / Q000187:drug effects* / Q000201:enzymology; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004247:DNA / Q000187:drug effects*; D004032:Diet; D004127:Dimethylhydrazines / Q000633:toxicity*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008763:Methylhydrazines / Q000633:toxicity*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D010088:Oxidoreductases / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D002250:Carbon Radioisotopes; D004127:Dimethylhydrazines; D005419:Flavonoids; D008763:Methylhydrazines; D019324:beta-Naphthoflavone; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase; D019813:1,2-Dimethylhydrazine