Immunosuppressive effects of benzidine in mice: evidence of alterations in arachidonic acid metabolism.
Benzidine (4,4'-diaminobiphenyl), a known human bladder carcinogen used in the synthesis of dyes, was immunosuppressive in mice after subchronic exposure. Suppression, particularly of cell-mediated immunity, occurred at dose levels previously found to be subtumorigenic in mice, as evidenced by suppressed lymphoproliferative and delayed hypersensitivity responses. In addition, benzidine exposure was found to decrease host resistance, including resistance to the growth of transplantable tumor cells and infection with Listeria. These data suggest that the development of neoplastic disease may be facilitated by the ability of benzidine to alter the immune response. The mechanism(s) responsible for immunosuppression by benzidine, however, is probably not the same as that responsible for its direct carcinogenicity. The addition of benzidine in vitro to mitogen-activated lymphocytes mimicked the suppression of lymphocyte responsiveness in vivo. In vitro studies suggested that alterations in metabolites of the arachidonic acid/lipoxygenase pathway were responsible for the immune alterations. Benzidine and the lipoxygenase inhibitor NDGA inhibited arachidonic acid metabolism and the mitogen response in lymphocytes, whereas the cyclooxygenase inhibitor indomethacin was ineffective. Addition of 8brcGMP partially restored benzidine-suppressed responses, whereas arachidonic acid potentiated the suppression. These data are consistent with the hypothesis that alterations in lymphocyte functions may occur as a result of quantitative changes or depletion of conversion products in the arachidonate/lipoxygenase pathway induced by the addition of compounds that serve as co-oxidative substrates for hydroperoxidases, the prototype being benzidine.
Luster
M I
MI
Tucker
A N
AN
Hayes
H T
HT
Pung
O J
OJ
Burka
T
T
McMillan
R
R
Eling
T
T
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D001560:Benzidines / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D001711:Biotransformation; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity*; D007694:Killer Cells, Natural / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D009368:Neoplasm Transplantation
D001095:Arachidonic Acids; D001560:Benzidines; D007166:Immunosuppressive Agents; D016718:Arachidonic Acid; C029876:benzidine; C016276:8-bromocyclic GMP; D006152:Cyclic GMP