Lack of correlation between formation of reactive metabolites and thymic atrophy caused by 3, 4, 3', 4'-tetrachlorobiphenyl in C57BL/6N mice.
The possible role of active metabolites of 3, 4, 3', 4'-tetrachlorobiphenyl (TCB) in causing thymic atrophy was investigated using inbred strains of mice. The generation of reactive species which bind covalently to cellular proteins was used to monitor the formation of active TCB metabolites. The amount of in vitro covalent binding of TCB to proteins by liver microsomes was increased markedly by pretreatment of AHH-responsive C57BL/6N mice with either 3-methylcholanthrene (MC) or TCB itself, although these two inducers were not effective in AHH-nonresponsive DBA/2N mice. MC treatment also caused an induction of microsomal TCB-binding activity in all of the (C57BL/6N X DBA/2N) F1 mice. Moreover, among 38 individuals of [(C57BL/6N) (DBA/2N) F1 X DBA/2N] backcross, 23 mice responded to MC with respect to microsomal TCB-binding activity while others did not. These results suggest that the conversion of TCB to protein-bound metabolites is mediated by particular form(s) of cytochrome P-450 which is (are) induced by an Ah receptor mechanism. In order to ascertain whether the active TCB metabolites play a role in causing thymic atrophy, 14C-labeled TCB was administered IP to C57BL/6N mice and the amount of covalent binding of radioactive metabolites to tissue proteins was determined. The in vivo binding was evident in the liver, particularly in the microsomal fraction, on the basis of protein content. In contrast, the thymic proteins contained no measurable amounts of bound radioactivity even when the mice showed marked thymic atrophy. These data suggest that thymic atrophy caused by TCB is not likely to result from the generation of reactive metabolites.
D000818:Animals; D001284:Atrophy / Q000139:chemically induced; D001711:Biotransformation; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000633:toxicity*; D011506:Proteins / Q000378:metabolism; D013950:Thymus Gland / Q000473:pathology*; D013997:Time Factors; D014018:Tissue Distribution
D011506:Proteins; D011078:Polychlorinated Biphenyls; C028451:3,4,3',4'-tetrachlorobiphenyl