- Monocrotaline (MCT) is a member of a class of naturally occurring
phytotoxins known as pyrrolizidine alkaloids (PAs). Exposure to PAs can result
in liver and cardiopulmonary lesions as well as lymphoid organ atrophy. In the
present study C57BI/6 (B6) mice received MCT (0-150 mg/kg/day, po) for 14
days. Overt toxicity was minimal and observed only at highly immunosuppressive
doses. Following MCT exposure, significant dose-dependent suppressions
were observed in the following immune responses: numbers of antibody
producing cells, cytotoxic T- lymphocyte activity, and NK cell cytotoxicity. The
antibody responses to the T cell-dependent antigen, SRBC, and the T cell-independent
(TI) antigens, DNP-Ficoll and TNP-LPS, were decreased with
identical dose response curves. This, along with data showing MCT decreased
blastogenesis of B cells more than T cells at the lowest dose level, and that high
doses induced significant decreases in the total number of B cells only, suggest
that the B cell may be more sensitive than T cells, NK cells , or macrophages.
The liver and lung toxicity of MCT is believed to be mediated through its
metabolism by mixed function oxidase (MFO) enzymes to reactive pyrroles
(monocrotaline pyrrole, MCTP; and dihydropyrrolizine, DHP). Accordingly, it
was our hypothesis that the immunotoxicity could be modulated by altering MFO
activity. To test this, mice were given a single dose of MCT (100 or 200 mg/kg,
po) after MFO induction with phenobarbital; in other experiments mice received
the MFO inhibitor chloramphenicol immediately before and 3 hrs after a single
exposure to MCT (300 mg/kg, po). However, neither MFO induction nor
inhibition significantly altered the immunosuppressive potency of MCT. The
antibody and blastogenic responses of splenic lymphocytes directly exposed to
MCT (1-3 mM) or MCTP (1-8 μM) in culture were inhibited in a concentration-dependent
manner, indicating that both parent and metabolite were immunotoxic.
However, the inability to alter the in vivo immunotoxicity by altering MFO
activity questions the role this metabolite may play in vivo. In conclusion, the
immune system in B6 mice is a sensitive target of MCT toxicity. Inhibition of
blastogenesis appears to be one mechanism of MCT-induced immunosuppression.
In contrast to other toxic effects of MCT, our results suggest that the parent
compound itself plays a significant role in the immunotoxicity.