The effect of dose and cytochrome P450 induction on the metabolism and disposition of the food-borne carcinogen 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx) in the rat.
The effect of dose and cytochrome P450 induction on the metabolism and disposition of the food-borne carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was investigated in the male Sprague-Dawley rat. Animals were given MeIQx by gavage at doses of 0.01, 0.2 or 20 mg/kg body wt. The phase II conjugates, MeIQx-N2 sulfamate and MeIQx-N2 glucuronide were the predominant metabolites found in urine of non-induced animals at the highest dose treatment. Animals induced with polychlorinated-biphenyl (PCB) produced greater amounts of metabolites hydroxylated at the 5 position of MeIQx which were excreted as glucuronide or sulfate conjugates. At the lowest dose studied, the urinary excretion profile was nearly identical for both animal groups and cytochrome P450 induction had little influence on metabolism. In contrast to high dose exposure, where sulfamate formation was a major route of detoxification, N2 glucuronide formation was the most important metabolic pathway for elimination of MeIQx at low doses. Liver microsomes transformed MeIQx to the genotoxic metabolite 2-hydroxyamino-3,8-dimethylimidazo[4,5-f]quinoxaline (HNOH-MeIQx) and N-hydroxylase activity was 20-fold greater in microsomes obtained from PCB-treated animals than in untreated control animals. The increase in N-hydroxylase activity was discerned in vivo through formation of the metastable N-glucuronide conjugate of HNOH-MeIQx (MeIQx-[HO-N]-Gl). This metabolite accounted for approximately 3% of the dose in bile of PCB-treated rats. In contrast, in the non-induced rat, MeIQx-[HO-N]-Gl was preferentially excreted in urine and accounted for approximately 0.2-1% of the total dose. These results demonstrate that the metabolism of MeIQx in the rat is influenced by both dose and cytochrome P450 induction. The absence of intestinal tumors in the non-induced rat may be partially attributed to the low levels of formation and poor biliary excretion of the N-glucuronide conjugate of the genotoxic metabolite HNOH-MeIQx.
Turesky
R J
RJ
Nestlé Research Centre, Nestec Ltd, Lausanne, Switzerland.
Markovic
J
J
Bracco-Hammer
I
I
Fay
L B
LB
D015057:1-Naphthylamine / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005243:Feces / Q000737:chemistry; D005965:Glucuronates / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009153:Mutagens / Q000378:metabolism / Q000493:pharmacokinetics*; D009596:Nitrophenols / Q000378:metabolism; D010084:Oxidation-Reduction; D011810:Quinoxalines / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013056:Spectrophotometry, Ultraviolet
D005965:Glucuronates; D009153:Mutagens; D009596:Nitrophenols; D011810:Quinoxalines; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D003577:Cytochrome P-450 Enzyme System; D015057:1-Naphthylamine; D014453:Glucuronosyltransferase; C024836:4-nitrophenol