Selective inhibition of arachidonate 5‐lipoxygenase by novel acetohydroxamic acids: biochemical assessment in vitro and ex vivo

Abstract

1 The chemically novel acetohydroxamic acids, BW A4C, BW A137C and BW A797C, are potent inhibitors of the synthesis of leukotriene B₄ (LTB₄) from arachidonic acid by human leucocyte homogenates: the concentrations required for 50% inhibition (IC₅₀) were 0.1 μm, 0.8 μm and 0.5μm respectively. Inhibition was less at higher concentrations of arachidonic add. 2 These compounds also inhibited the synthesis of [¹⁴C]-5-HETE from [¹⁴C]-arachidonic acid and the calcium-dependent synthesis of LTB₄ from 5-HPETE. This, therefore, suggests that they inhibit 5-lipoxygenase and LTA₄ synthase. 3 Concentrations of acetohydroxamic acids required to inhibit metabolism of arachidonic acid by cyclo-oxygenase, 12-lipoxygenase and 15-lipoxygenase were 10 to 100 times higher than those required to inhibit 5-lipoxygenase. 4 The compounds were potent inhibitors of LTB₄ synthesis induced by the ionophore, A23187, in human intact leucocytes. This inhibition was reversed by washing the cells. They were also potent, selective inhibitors of LTB₄ synthesis induced by A23187 in whole rat blood: binding to rat plasma proteins did not greatly reduce the effectiveness of the compounds. 5 The effects of the acetohydroxamic acids, administered either intravenously or orally to rats, on the synthesis of LTB₄, and thromboxane B₂ (TXB₂) in A23187-stimulated blood ex vivo was studied. The three compounds caused dose-dependent inhibition of the synthesis of LTB₄ but not TXB₂. Inhibition of LTB₄ synthesis persisted for up to 6 h after a single oral dose of 50 mg kg⁻¹. 6 The plasma concentrations of unchanged compound determined by h.p.l.c. correlated with the inhibition of LTB₄ synthesis ex vivo.