MEIQX-DNA ADDUCT FORMATION IN RODENT AND HUMAN TISSUES AT LOW-DOSES

Heterocyclic amines, such as 2-amino-3,8-dimethylimidazo[4,5-f]quinoxa line (MeIQx), are mutagenic/carcinogenic compounds formed during the c ooking of protein-rich foods. Human exposure to MeIQx has been estimat ed to range from ng/person/day to a few mu g/person/day. In contrast, animal studies have been conducted at doses in excess of 10 mg/kg/day. In order to determine the relevance of high-dose animal data for huma n exposure, the dose-response curves for [C-14]-MeIQx have been determ ined in rodents at low doses under both single-dose and chronic dosing regimens using the high sensitivity of accelerator mass spectrometry (AMS). To make a direct species comparison, rodent and human colonic M eIQx-DNA adduct levels have been compared following oral administratio n of [C-14]-MeIQx. The results of these studies show: (1) total MeIQx levels are highest in the liver >> kidney > pancreas > intestine > blo od; (2) MeIQx levels in the liver plateau after 7 days of chronic feed ing; (3) hepatic MeIQx-DNA adducts begin to plateau after 2-4 weeks an d reach steady-state levels between 4 and 12 weeks on chronic exposure s; (4) hepatic DNA adducts generally increase as a linear function of administered dose for a single-dose exposure and as a power function f or chronic feeding over a dose range spanning 4 orders of magnitude; ( 5) human colon DNA adduct levels are similar to 10 times greater than in rodents at the same dose and time point following exposure; and(6) greater than or equal to 90% of the MeIQx-DNA adduct in both rodent an d human colon appears to be the dG-C8-MeIQx adduct. These studies show that MeIQx is readily available to the tissues for both humans and ro dents and that adduct levels are generally linear with administered do se except at high chronic doses where adduct levels begin to plateau s lightly. This plateau indicates that linear extrapolation from high-do se studies probably underestimates the amount of DNA damage present in the tissues following low dose. Further, if adducts represent the bio logically effective dose, these data show that human colon may be as s ensitive to the genotoxic effects of MeIQx as rat liver. The significa nce of these endpoints to tumor response remains to be determined.