METABOLIC-ACTIVATION OF HETEROCYCLIC AMINE FOOD MUTAGENS IN THE MAMMARY-GLAND OF LACTATING FISCHER-344 RATS

We investigated the ability of the mammary gland to metabolically acti vate 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethy limidazo[4,5-f]-quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimida zo[4,5-b]pyridine (PhIP). Although mammary gland microsomes had almost no capacity to metabolically activate the parent compounds, mammary g land cytosol was able to esterify the N-hydroxylamines. Acetyltransfer ase was the primary enzyme responsible for the phase II activation of the N-hydroxylamines. The level of acetyl CoA-stimulated binding when N-hydroxy PhIP served as the substrate was approximately 3- and 17-fol d higher than when IQ and MeIQx served as substrates, respectively. N- Hydroxy-IQ and N-hydroxy PhIP can also be activated by tRNA synthetase and phosphatase, but not by sulfotransferase. However, the levels of proline- and ATP-enhanced DNA binding was approximately 30- and 60-fol d lower than the acetyl CoA-enhanced DNA binding of lQ and PhIP, respe ctively. Differences observed in the phase II activation of the variou s heterocyclic amines in the mammary gland may explain why the mammary gland is a target organ for PhIP-induced carcinogenicity but not for IQ- or MeIQx-induced carcinogenicity in Fischer 344 rats.