Covalent binding of 7,12-dimethylbenz[ a]anthracene to lymphoid and nonlymphoid tissues following oral administration to B6C3F1 mice

Abstract

Previous studies have shown that 7,12-dimethylbenz[ a]anthracene (DMBA) is cytotoxic to various murine lymphoid tissues, including the spleen, thymus, mesenteric lymph nodes (MLNs), and Peyer's patches (PPs). In the present studies, we measured the amount of covalent binding of [ 3H]DMBA to lymphoid and nonlymphoid tissues and correlated these findings with the overall levels of [ 3H]DMBA (and derived substances) present in various tissues following a single oral administration to mice. Results show that [ 3H]DMBA was taken up relatively rapidly from the GI tract and that it was nearly completely eliminated within 24 hr via the feces. Peak plasma levels were obtained approximately 6 hr after gavage, and most organs (including brain, heart, liver, lung, kidney, spleen, and thymus) achieved their peak level of DMBA at this time. Maximal concentrations of DMBA were detected in gut-associated lymphoid tissues (i.e., PPs and MLNs) at 4 hr, during which time covalent binding of [ 3H]DMBA was also maximal. The time course for covalent binding was different in the liver, lung, thymus, and spleen, peaking at 6–12 hr. The amount of covalent binding of [ 3H]DMBA and derived metabolites in the spleen was more than twice that seen in the other tissues examined. Since the spleen has previously been found to be less sensitive to DNA fragmentation induced by DMBA than the PPs, these results suggest that covalent binding may not be the primary determinant of lymphotoxicity in these organs.