Characterization of the benzodiazepine binding site (diazepam site) on human serum albumin.

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Abstract
The benzodiazepine-binding site (diazepam site) was investigated by studying the interaction between benzodiazepine and bilirubin in binding to human serum albumin (HSA). This paper reports some experimental observations supporting the assumption that the diazepam site on HSA is better described as the diazepam site-Site II overlapping area, consisting of the diazepam site and Site II. The fact that the binding of benzodiazepines to HSA was inhibited by Site II drugs but was not affected by bilirubin suggests that the diazepam site is the same as or very close to Site II, but is independent of the bilirubin site. When 1 or 2 mol of benzodiazepines per mol of HSA was added to bilirubin-HSA complex (0.6:1), the amount of bound bilirubin increased and the extrinsic Cotton effect of bilirubin-HSA complex was also strengthened. On the other hand, 1 or 2 mol of Site II drugs did not affect bilirubin-HSA complex. These apparently conflicting observations can be explained by assuming that the diazepam site and Site II overlap each other and the diazepam site acts cooperatively with the bilirubin site through an allosteric effect. The binding of benzodiazepines to the diazepam site of HSA may cause limited conformational changes around the bilirubin site.