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N-Oxidative Metabolism of 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in Humans Excretion of the N^2-Glucuronide Conjugate of 2-Hydroxyamino-MeIQx in Urine¹

Division of Bioengineering and Environmental Health [W. G. S., S. R. T.] and Department of Chemistry [S. R. T.], Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; Nestlé Research Center, Nestec Limited, 1000 Lausanne 26, Switzerland [R. J. T.]; and Nutritional Epidemiology Branch, National Cancer Institute, NIH, Rockville, Maryland 20892 [R. S.]

2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a major heterocyclic aromatic amine (HAA) formed in cooked meats, is metabolically transformed to mutagenic/carcinogenic intermediates. Cytochrome P4501A2 (CYP1A2)-mediated N-hydroxylation followed by phase II O-esterification by N-acetyltransferase (NAT2) are generally regarded as activation processes in which MeIQx and other HAAs are converted to genotoxic species. Inthis study, we determined the relationship between the activities of these two enzymes and the urinary excretion level of the N²-glucuronide conjugate of 2-hydroxyamino-MeIQx—N²-(-1-glucosiduronyl)-2-hydroxyamino-3,8-dimethylimidazo[4,5-f]quinoxaline (N-OH-MeIQx-N²-glucuronide)—among healthy subjects fed a uniform diet containing high-temperature cooked meat. The individuals (n = 66) in the study ate meat containing known amounts of MeIQx, and urine was collected from 0 to 12 h after the meal. After addition of the deuterium-labeled internal standard to urine, N-OH-MeIQx-N²-glucuronide was isolated using solid-phase extraction and immunoaffinity separation. The isolated conjugate was converted to the deaminated product 2-hydroxy-3,8-dimethylimidazo[4,5-f]quinoxaline (2-OH-MeIQx) by heating with acetic acid. 2-OH-MeIQx and its deuterated analogue were derivatized to form the corresponding 3,5-bis(trifluoromethyl)benzyl ether derivatives and analyzed by capillary gas chromatography-negative ion chemical ionization mass spectrometry using selected ion monitoring procedures. The subjects in the study excreted an average of 9.4 ± 3.0% (±SD) of an ingested dose of MeIQx as N-OH-MeIQx-N²-glucuronide in urine; the range varied from 2.2 to 17.1%. A significant correlation was found between the level of N-OH-MeIQx-N²-glucuronide in urine and the amount of MeIQx ingested (r_s = 0.44; P = 0.0002). The excretion level of N-OH-MeIQx-N²-glucuronide in urine was not associated with the enzyme activities of NAT2 or CYP1A2. This is expected with the latter enzyme because the metabolism of MeIQx is first order and very rapid at the amounts ingested. The amount of N-OH-MeIQx-N²-glucuronide in urine was not correlated with the age or sex of the individuals. Our results indicate that biotransformation of MeIQx via CYP1A2 oxidation to form the N-hydroxylamine followed by N²-glucuronidation is a general pathway of MeIQx metabolism in humans; the variability in the excreted levels of N-OH-MeIQx-N²-glucuronide is probably due to interindividual differences in UDP-glucuronosyltransferase activity and/or excretion pathways.

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