Abacavir and warfarin modulate allosterically kinetics of NO dissociation from ferrous nitrosylated human serum heme-albumin

Human serum albumin (HSA) participates to heme scavenging, in turn HSA-heme binds gaseous diatomic ligands at the heme-Fe-atom. Here, the effect of abacavir and warfarin on denitrosylation kinetics of HSA-heme Fe(II)-NO (i.e., k(off)) is reported. In the absence of drugs, the value of k(off) is (1.3 +/- 0.2) x 10(-4) s(-1). Abacavir and warfarin facilitate NO dissociation from HSA-heme-Fe(II)-NO, the k(off) value increases to (8.6 +/- 0.9) x 10(-4) s(-1). From the dependence of k(off) on the drug concentration, values of the dissociation equilibrium constant for the abacavir and warfarin binding to HSA-heme-Fe(II)-NO (i.e., K = (1.2 +/- 0.2) x 10(-3) M and (6.2 +/- 0.7) x 10(-5) M, respectively) were determined. The increase of koff values reflects the stabilization of the basic form of HSA-heme-Fe by ligands (e.g., abacavir and warfarin) that bind to Sudlow's site I. This event parallels the stabilization of the six-coordinate derivative of the HSA-heme-Fe(II)-NO atom. Present data highlight the allosteric modulation of HSA heme-Fe(II) reactivity by heterotropic effectors. (c) 2008 Elsevier Inc. All rights reserved.