Recovery of dimethylnitrosamine-induced immunosuppression by pargyline in the mixed cultures of murine hepatocytes and splenocytes.
To investigate the role of monoamine oxidase (MAO) in dimethylnitrosamine (DMN)-induced suppression of the antibody response to sheep erythrocytes, the effect of an MAO inhibitor, pargyline, was studied in mixed cultures of murine hepatocytes and splenocytes. When pargyline was added simultaneously with DMN during the coculture, DMN-induced immunosuppression was clearly recovered dose-dependently. Cyclophosphamide was used as a comparative control in these studies. Surprisingly, pargyline also reversed cyclophosphamide-induced suppression of the antibody response in the coculture system. The results with cyclophosphamide were not consistent with a role by MAO, and suggested that pargyline may not be selective for MAO. To confirm our hypothesis, the ability of pargyline to inhibit three cytochrome P-450 (P-450) isozyme-specific monooxygenase activities in vitro was studied using mouse liver microsomes. Pargyline, under the same concentration ranges that we used in the coculture studies, clearly inhibited the P-450IIE1-specific p-nitrophenol hydroxylase activity and P-450IIB1-specific pentoxyresorufin O-dealkylase activity. Taken together, our present results indicate that pargyline inhibits P-450 activity and is not selective for MAO. Although further studies are required to confirm a possible role by MAO in DMN-induced immunosuppression, our results suggest that pargyline may recover DMN-induced immunosuppression by primarily inhibiting the ability of P-450 enzymes in hepatocytes to activate DMN to its immunosuppressive metabolite(s).
Jeong
T C
TC
Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298.
Yang
K H
KH
Holsapple
M P
MP
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001711:Biotransformation; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004128:Dimethylnitrosamine / Q000493:pharmacokinetics / Q000633:toxicity*; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism / Q000502:physiology; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010293:Pargyline / Q000494:pharmacology*; D012756:Sheep; D013154:Spleen / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D010293:Pargyline; D008995:Monoamine Oxidase; D004128:Dimethylnitrosamine