1. The metabolism of irsogladine (ISG) was studied in hepatic microsomes from the rat, dog, monkey and man, and marked species differences were observed in N-oxidation of ISG. The rank order of the activity of the N-oxidation was shown to be man < monkey < dog < rat. 2. Anti-NADPH-P450 reductase antibody inhibited the formation of the N-oxidized metabolite of ISG (ISG-N-oxide) in hepatic microsomes from rats by 74%. Anti-CYP2C11 antibody also inhibited the formation of ISG-N-oxide in hepatic microsomes from rat by 73%, whereas anti-CYP2E1, 3A2 and 4A1 antibody did not inhibit N-oxidation. Thus, CYP2C11 in the rat is at least partially responsible for the N-oxidation of ISG in the rat. 3. Anti-CYP2C11 antibody also inhibited the formation of ISG-N-oxide in hepatic microsomes from the dog and monkey by 61 and 46% respectively. Therefore, a isoform(s) similar to CYP2C11 partially contributed to the N-oxidation of ISG in the dog and monkey. In contrast, human CYP2C9, a member of the human CYP2C subfamily, did not catalyse the N-oxidation of ISG. 4. These findings show that the marked species difference in the N-oxidation of ISG is caused by the difference in the catalytic properties of CYP2C among the species examined.
Alloantigens are recognized by T cells either through a direct pathway, which involves recognition of alloantigens expressed on allogeneic antigen-presenting cells (APC), or through an indirect pathway, which involves recognition of processed alloantigens presented by self APC. We investigated whether rat xenoantigens are also recognized by direct (xenogeneic APC-restricted) and/or indirect (self APC-restricted) pathways. C57BL/6 (B6) mouse anti-F344 or WKAH rat mixed lymphocyte reactions (MLRs) were partially inhibited by addition of either anti-mouse CD4 or CD8 monoclonal antibody (mAb) and almost completely blocked in the presence of both mAbs. These xenogeneic MLRs were almost completely inhibited by simultaneous depletion of both self and xeno APCs and only partially suppressed by the elimination of either type of APC, indicating that freshly prepared splenic mouse T cells can recognize rat xenoantigens through both direct and indirect pathways. Anti-F334 T cell lines were generated from B6 anti-F344 MLR cultures, and four CD4+ and four CD8+ T cell clones were isolated from these parental lines. The parental lines and those derived T cell clones were tested for their ability to proliferate depending on the presence of F344 APC. Proliferation of CD8 clones by stimulation with F344 APC was inhibited by the addition of anti-rat class I MHC mAb but not of anti-class II MHC mAbs. Conversely, proliferation of CD4 clones was reduced by addition of anti-class II MHC mAbs. Thus, these results indicate that xeno (rat)-reactive mouse T cells recognize xenoantigens via both indirect (self APC-restricted) and direct (xeno APC-restricted) pathways and that both CD4 and CD8 subsets of T cells participate in a direct pathway of xenoantigen recognition.
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