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 urine
Wg. Stillwell et al., 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 urine, CANCER RES, 59(20), 1999, pp. 5154-5159
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)-mediat
ed N-hydroxylation followed by phase II O-esterification by N-acetyltransfe
rase (NAT2) are generally regarded as activation processes in which MeIQx a
nd other HAAs are converted to genotoxic species, In this study, we determi
ned the relationship between the activities of these two enzymes and the ur
inary excretion level of the N-2-glucuronide conjugate of 2-hydroxyamino-Me
IQx-N-2-(beta-1-glucosiduronyl)-2-hydroxyamino-3,8- dimethylimidazo[4,5-f]q
uinoxaline (N-OH-MeIQx-N-2-glucuronide)-among healthy subjects fed a unifor
m diet containing high-temperature cooked meat, The individuals (n = 66) in
the study ate meat containing known amounts of MeIQx, and urine was collec
ted from 0 to 12 h after the meal. After addition of the deuterium-labeled
internal standard to urine, N-OH-MeIQx-N-2-glucuronide was isolated using s
olid-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(trif
luoromethyl)benzyl ether derivatives and analyzed by capillary gas chromato
graphy-negative ion chemical ionization mass spectrometry using selected io
n 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-N-2-glucuron
ide in urine; the range varied from 22 to 17.1%. A significant correlation
was found between the level of N-OH-MeIQx-N-2-glucuronide in urine and the
amount of MeIQx ingested (r(s) = 0.44; P = 0.0002), The excretion level of
N-OH-MeIQx-N-2-glucuronide in urine was not associated with the enzyme acti
vities of NAT2 or CYP1A2. This is expected with the latter enzyme because t
he metabolism of MeIQx is first order and very rapid at the amounts ingeste
d, The amount of N-OH-MeIQx-N-2-glucuronide in urine was not correlated wit
h the age or sex of the individuals, Our results indicate that biotransform
ation of MeIQx via CYP1A2 oxidation to form the N-hydroxylamine followed by
N-2-glucuronidation Is a general pathway of MeIQx metabolism in humans; th
e variability in the excreted levels of N-OH-MeIQx-N-2-glucuronide is proba
bly due to interindividual differences in UDP-glucuronosyltransferase activ
ity and/or excretion pathways.