Effects of fatty acid on the specific drug-binding sites of human serum albumin.

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Abstract
The effects of various fatty acids on the ligand-binding sites of human serum albumin (HSA) were investigated. The present results provide evidence for the independence of the four classified binding sites and for the existence of distinct high-affinity sites for long-chain (C12.sbd.C18) and for medium-chain (C6.sbd.C10) fatty acids. The binding of long-chain fatty acids to HSA at low molar ratios (0.5.sbd.2.0) of fatty acids to HSA caused marked conformational changes. Site I and the bilirubin-site were sensitive to these conformational changes: Site I became asymmetrical and the bilirubin-site acquired a cooperative nature. On the other hand, the diazepam-site and Site II were little affected. The binding of medium-chain fatty acids to HSA at low molar ratios (vide supra) caused competitive ligand displacement. These acids did not change the conformation of HSA, but they perturbed Site II to a limited extent, marking Site II more asymmetric. These effects enhanced the circular dichroism spectrum of flufenamic acid-HSA complex. These results confirmed that the diazepam-site and Site II are distinct sites. At a high molar excess (4.0-8.0) of fatty acid to HSA, the binding of ligands to HSA was inhibited in a complicated manner that appeared to reflect a combination of competitive effects and conformational changes.