Effect of 3-methylcholanthrene induction on the distribution and DNA adduction of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in F344 rats.
3-Methylcholanthrene (3MC) is a potent inducer of the cytochrome P450IA family of enzymes that catalyses the metabolic activation of the food mutagen/carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). We have examined the effect of pretreatment with 3MC on the distribution and DNA adduct formation of IQ in male Fischer F344 rats. 3 hr after a single dose of [14C]IQ (10 mg/kg body weight, by gavage), the level of radioactivity in extrahepatic tissues was 30-70% less in 3MC-pretreated rats than in vehicle control rats. Although the level of radioactivity in the liver did not change after 3MC pretreatment, IQ-DNA adduct levels, measured by the 32P-postlabelling method, were 60% lower in the livers of 3MC-pretreated rats than those of control rats, and 83-97% lower in extrahepatic tissues such as the kidneys, colon, small intestine, bladder, heart and lung. IQ-DNA adducts in the testes and brain were found in control rats but were not detected in 3MC-pretreated rats. The rate of removal of IQ-DNA adducts from the livers of control and 3MC-pretreated animals was the same from 3 to 48 hr. At 48 hr, the adduct level in 3MC-pretreated rats remained lower than that seen in the control rats. The data suggest that 3MC induction of the P450IA family of cytochromes in vivo results in an increased rate of IQ detoxification.
Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, MD 20892.
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Snyderwine
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Nouso
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Schut
D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D009153:Mutagens / Q000493:pharmacokinetics* / Q000633:toxicity; D010088:Oxidoreductases / Q000096:biosynthesis*; D011804:Quinolines / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D002273:Carcinogens; D009153:Mutagens; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D008748:Methylcholanthrene; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1