The disposition and metabolism of 2-amino-3-methylimidazo-[4,5-f]quinoline in the F344 rat at high versus low doses of indole-3-carbinol.
Indole-3-carbinol (I3C), a compound found in cruciferous vegetables, inhibits the formation of DNA adducts, colonic aberrant crypts, and tumors in rats given heterocyclic amines, such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Previous mechanism studies indicated that I3C induces cytochromes P4501A1 (CYP1A1) and CYP1A2, as well as phase 2 pathways, leading to enhanced metabolism and excretion of IQ. However, the chemopreventive activity is dependent on the dose of I3C, and at low doses which do not induce CYP1A activity, there is evidence for increased IQ-DNA adduct formation in vivo. The present study examined the fate of IQ in the rat and the profile of urinary metabolites across a broad range of I3C doses. Male F344 rats were given a single injection of I3C by oral gavage, at a dose equivalent to that received from a single daily exposure to 0, 5, 10, 25, 50, 100, 200, 500 or 1000 ppm I3C in the diet, or they were given the 1000-ppm-equivalent dose of I3C for 14 consecutive days. Subsequently, each rat was given 14C-labeled IQ (5 mg/kg; 0.1 mCi/kg) and the animal was sacrificed 8 h later. With increasing I3C, there was a dose-dependent decrease in IQ-associated radiolabel in several systemic tissues, and an increase in the radiolabel eliminated via the feces. In the urine, there was a dose-dependent increase in IQ-5-O-glucuronide and IQ-5-O-sulfate metabolites, and a concomitant decrease in the IQ-sulfamate at intermediate and high doses of I3C. However, 5- and 10 ppm-equivalent doses of I3C enhanced the levels of IQ-sulfamate compared with controls, possibly due to the high ratio of hepatic CYP1A2 versus CYP1A1 activities at these I3C doses. The possible significance of the low versus high dose effects are discussed in the context of ongoing clinical trials with I3C and the reported chemopreventive mechanisms in vivo.
Dashwood
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Linus Pauling Institute, and Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR 97331-6512, USA. rod.dashwood@oregonstate.edu
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D000284:Administration, Oral; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D002273:Carcinogens / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018890:Chemoprevention; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D014018:Tissue Distribution
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D007211:Indoles; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C016517:indole-3-carbinol