FARNESYL-L-CYSTEINE ANALOGS CAN INHIBIT OR INITIATE SUPEROXIDE RELEASE BY HUMAN NEUTROPHILS

A series of farnesylcysteine analogs was studied with respect to their abilities to interfere with fMet-Leu-Phe (fMLP)-stimulated superoxide (O-2(radical-anion)) release by human neutrophils. Simple acyl deriva tives of farnesyl-L-cysteine, such as the N-acetyl (L-AFC) and N-isobu tyryl derivatives (L-iBFC), which are substrates for the isoprenylated protein methyltransferase, can block O-2(radical-anion) release. The N-butyryl analog (L-BFC), which is an isomer of L-iBFC and also a subs trate for the methyltransferase, does not inhibit O-2(radical-anion) r elease but actually stimulates it in the absence of fMLP. Other analog s, including the N-pivaloyl derivative, which has been found to be nei ther a substrate nor an inhibitor of methyltransferase, also stimulate very large quantities of O-2(radical-anion) production. The stimulato ry effects of these derivatives are saturable and exquisitively sensit ive to small structural changes in the analogs. The signal transductio n pathway(s) utilized by pivaloyl derivatives for triggering O-2(radic al-anion) generation is very similar to that employed by fMLP. These d ata make it clear that farnesyl-L-cysteine analogs do not produce thei r pharmacological effects in neutrophils via methyltransferase blockad e. This could be further demonstrated by showing that sinefungin and S -adenosylhomocysteine, both powerful and general methyltransferase inh ibitors which bind at the S-adenosylmethionine site, had no effect in preventing the increased oxygen consumption associated with O-2(radica l-anion) production in permeabilized neutrophils. These studies reveal that farnesyl-L-cysteine analogs interact with a hitherto undefined t arget in neutrophils that may be exploited for inhibiting or stimulati ng the inflammatory or antimicrobial responses of these cells.