DIFFERENTIAL SUSCEPTIBILITY OF FILARIAL AND HUMAN ERYTHROCYTE GLUTATHIONE-REDUCTASE TO INHIBITION BY THE TRIVALENT ORGANIC ARSENICAL MELARSEN OXIDE

The glutathione reductases (GR) from two cattle filariae (Setaria digi tata and Onchocerca gutturosa) have been isolated and their properties have been compared to those of human erythrocyte GR. In general, the enzymes appear to be very similar with respect to substrate-specificit y for glutathione disulfide and NADPH, molecular mass (97 kDa vs. 98 k Da) and oligomeric organisation (subunit size of 51 kDa vs. 50 kDa). H owever, studies on the inhibition of the enzymes by the trivalent mela minophenyl arsenical melarsen oxide revealed that the human GR is less susceptible to inhibition by the arsenical than the filarial enzymes. Further, it was found that the mechanism of inactivation differs for the host and filarial enzymes. The human enzyme is inhibited by melars en oxide in a competitive manner with a K-i of 23.7 mu M, whereas the filarial GRs are inhibited in two stages: an immediate partial inactiv ation followed by a time-dependent stage with saturable pseudo-first-o rder kinetics. K-i values for the S. digitata and O. gutturosa GRs are 38.3 mu M and 4.5 mu M, respectively, with maximum second-stage inact ivation rates of 1.0 X 10(-4) s(-1) and 24.3 X 10(-4) s(-1), respectiv ely. These differences between host and parasite enzyme might reflect differences in the primary and secondary structure of the proteins whi ch might be exploitable for the design of new specific macrofilaricida l drugs.