Effects of methyl substitutions on benz[a]anthracene derivatives-induced immunosuppression.
Polycyclic aromatic hydrocarbons are ubiquitous environmental contaminants known to be carcinogenic as well as immunosuppressive. Structure-activity studies have demonstrated that modifications in the number of methyl groups of benzanthracenic compounds lead to major changes in their biological activities such as induction of tumors. In the present study, we investigated the immunosuppressive effects of three benzanthracene derivatives differing by number or position of methyl radicals. 7,12-Dimethylbenz[a]anthracene, 12-methylbenz[a]anthracene, and 7-methylbenz[a]anthracene were tested for their ability to inhibit T-cell proliferation. For this purpose, we employed an in vitro activation model utilizing concanavalin A (ConA) or anti-CD3 monoclonal antibody (anti-CD3 mAb) to induce proliferation of murine T-lymphocytes from B6C3F1 mice. The three compounds inhibited splenocyte proliferation stimulated with anti-CD3 mAb, whereas DMBA and 12-MBA, but not 7-MBA, inhibited ConA-induced lymphoproliferation. Results concerning parameters involving interleukin-2 (IL-2) were correlated with those obtained for lymphoproliferation. IL-2 production and number of IL-2 receptors (IL-2R) per cell were inhibited by the three molecules tested, except for IL-2 production following ConA activation of cells treated with 7-MBA. Only DMBA profoundly affected IL-2 responsiveness, suggesting that this compound may inhibit both G0 to G1 and G1 to S transitions of the cell cycle. Addition of exogenous cytokines such as IL-1 and IL-6 with IL-2, or IL-2 alone, suggested that, for the three compounds tested, IL-1 and IL-6 production are not involved in benz[a]anthracene-induced immunosuppression. These results demonstrate that methylation at both 7 and 12 positions of the benzanthracene ring significantly enhances immunosuppression. In addition, DMBA may act on signal transduction mediated by the T-cell receptor (TCR) and the IL-2R, while this is not the case for 7-MBA and 12-MBA.
Saas
P
P
Laboratoire d'Immunotoxicologie et de Cancérogenèse, Faculté de Pharmacie Paris-Sud, Chatenay-Malabry, France.
Bohuon
C
C
Pallardy
M
M
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D000911:Antibodies, Monoclonal; D001551:Benz(a)Anthracenes / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D017252:CD3 Complex / Q000276:immunology; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003208:Concanavalin A / Q000633:toxicity; D005260:Female; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D007928:Lethal Dose 50; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000139:chemically induced; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
D000911:Antibodies, Monoclonal; D001551:Benz(a)Anthracenes; D017252:CD3 Complex; D002273:Carcinogens; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D007376:Interleukin-2; D015850:Interleukin-6; D015375:Receptors, Interleukin-2; D003208:Concanavalin A; D015127:9,10-Dimethyl-1,2-benzanthracene; C021220:12-methylbenzanthracene; C030935:benz(a)anthracene