Inhibition of CYP2E1 reverses CD4(+) T-cell alterations in trichloroethylene-treated MRL+/+ mice

Trichloroethylene is an organic solvent that is primarily used as a degreas ing agent for metals. There is increasing evidence in both humans and anima l models that trichloroethylene promotes the development of autoimmunity, b ut little is known about the mechanisms that mediate the effect of trichlor oethylene on the immune system. Metabolic activation of trichloroethylene i s considered an obligatory pathway for other known toxicities such as hepat otoxicity, nephrotoxicity, and carcinogenicity. Trichloroethylene is metabo lized by the cytochromes P450, primarily cytochrome P450 2E1 (CYP2E1). To i nvestigate whether metabolism by CYP2E1 is required for immunomodulation, w e treated autoimmune prone MRL+/+ mice with trichloroethylene in the drinki ng water for 4 weeks, in the presence or absence of diallyl sulfide, a spec ific inhibitor of CYP2E1. Using an antibody that recognizes proteins covale ntly modified by a reactive metabolite of trichloroethylene; two immunoreac tive proteins were detected in liver microsomes from trichloroethylene-trea ted mice. Formation of these trichloroethylene-protein adducts, an indicato r of metabolic activation, was completely inhibited in animals that were co ncomitantly treated with trichloroethylene and diallyl sulfide. The level o f CYP2E1 apoprotein in liver microsomes was significantly reduced in the pr esence of diallyl sulfide. The enhanced mitogen-induced proliferative capac ity of T cells from trichloroethylene-treated MRL+/+ mice was inhibited if the mice were also treated with diallyl sulfide. In addition, the reduction in interleukin-4 Levels secreted by activated CD4(+) T cells from trichlor oethylene-treated mice was reversed if the mice were also treated with dial lyl sulfide. Taken collectively, metabolism of trichloroethylene by CYP2E1 is responsible, at least in part, for the CD4(+) T cell alterations associa ted with exposure to this environmental toxicant.