Covalent binding of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline to albumin and hemoglobin at environmentally relevant doses. Comparison of human subjects and F344 rats.
Covalent binding of the food-borne heterocyclic amine 2-amino-3, 8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) to albumin and hemoglobin (Hb), 3.5-6.0 hr after oral administration of a single dose of either 21.3 or 228.0 microg of [14C]MeIQx (304 and 3257 ng/kg of body weight, respectively, based on a 70-kg subject weight), was studied in human volunteers using accelerator mass spectrometry. Human protein adduct levels were compared with data obtained for male F344 rats 4.5 hr after oral administration of 0.94-11,420 ng/kg of body weight [14C]MeIQx. Dose-dependent levels of MeIQx-albumin and MeIQx-Hb adducts were detected in both humans and rats. In each case, the regression coefficient (slope) of the dose-response curve was approximately 1. The highest levels of adduct formation per unit dose of MeIQx occurred with human albumin, followed by rat albumin, human Hb, and rat Hb (in that order). Although the human subjects were elderly and underwent colon resection surgery during the study period, the results indicate that formation of albumin and Hb adducts is dose dependent and that a trend exists for higher adduct levels per unit dose in humans, compared with F344 rats. Furthermore, MeIQx-albumin adducts are likely to provide a more sensitive marker of exposure to MeIQx than are MeIQx-Hb adducts.
Dingley
K H
KH
Biology and Biotechnology Research Program and Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, CA 94551-9900, USA.
Freeman
S P
SP
Nelson
D O
DO
Garner
R C
RC
Turteltaub
K W
KW
D000328:Adult; D000368:Aged; D000818:Animals; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D011485:Protein Binding; D011810:Quinoxalines / Q000097:blood*; D051381:Rats; D011916:Rats, Inbred F344; D012680:Sensitivity and Specificity; D012709:Serum Albumin / Q000378:metabolism*
D002250:Carbon Radioisotopes; D002273:Carcinogens; D006454:Hemoglobins; D011810:Quinoxalines; D012709:Serum Albumin; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline