Neonicotinoid trapping by the FA1 site of human serum albumin

Abstract

Neonicotinoids are a widely used class of insecticides that target the acetylcholine recognition site of the nicotinic acetylcholine receptors in the central nervous system of insects. Although neonicotinoids display a high specificity for insects, their use has been recently debated since several studies led to the hypothesis that they may have adverse ecological effects and potential risks to mammals and even humans. Due to their hydrophobic nature, neonicotinoids need specific carriers to allow their distribution in body fluids. Human serum albumin (HSA), the most abundant plasma protein, is a key carrier of endogenous and exogenous compounds. The in silico docking and ligand binding properties of acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam to HSA are here reported. Neonicotinoids bind to multiple fatty acid (FA) binding sites, preferentially to the FA1 pocket, with high affinity. Values of the dissociation equilibrium constant for neonicotinoid binding FA1 of HSA (i.e., calcKn) derived from in silico docking simulations (ranging between 3.9 × 10−5 and 6.3 × 10−4 M) agree with those determined experimentally from competitive inhibition of heme‐Fe(III) binding (i.e., expKn; ranging between 2.1 × 10−5 and 6.9 × 10−5 M). Accounting for the HSA concentration in vivo (~7.5 10−4 M), values of Kn here determined suggest that the formation of the HSA:neonicotinoid complexes may occur in vivo. Therefore, HSA appears to be an important determinant for neonicotinoid transport and distribution to tissues and organs, particularly to the liver where they are metabolized.

Binding of direct oral anticoagulants to the FA1 site of human serum albumin

“…In fact, the toxicity of DOACs depends upon several factors such as their transport to the liver by HSA and their CYP‐dependent hepatic metabolism. Since HSA is the most important carrier of xenobiotics in human plasma, 16,35,60 binding of DOACs to the FA1 site may significantly alter their free levels in plasma. In fact, conditions associated to changes of HSA plasma levels (i.e., increase under dehydration conditions and decrease in analbuminemic patients) may appreciably affect pharmacokinetic and pharmacodynamic properties of DOACs.…”

“…In the absence and presence of apixaban, betrixaban, dabigatran, dabigatran etexilate, edoxaban, and rivaroxaban, heme‐Fe(III) binding to HSA was followed spectrophotometrically between 370 and 450 nm, at pH 7.3 (2.0 × 10 −2 M phosphate buffer) and 20.0°C 16,29,31‐36 . The heme‐Fe(III) concentration was 1.2 × 10 −6 M, the DOAC concentration ranged between 1.0 × 10 −5 M and 5.0 × 10 −5 M, and the HSA concentration ranged between 1.3 × 10 −7 M and 5.0 × 10 −5 M. Heme‐Fe(III) binding to HSA, in the absence and presence of DOACs, was investigated at a fixed low heme‐Fe(III) concentration by increasing the amount of HSA 33,35 …”

“…In the absence and presence of apixaban, betrixaban, dabigatran, dabigatran etexilate, edoxaban, and rivaroxaban, values of the dissociation equilibrium constant for heme‐Fe(III) binding to HSA (ie, K h 0 and K h app , respectively; see Scheme 1) were obtained spectrophotometrically from the dependence of the relative absorbance intensity change (ie., Δ A /Δ A max ) of HSA:heme‐Fe(III) complex formation on the free HSA concentration (ie, [HSA]), according to Equation (1) 16,29,32‐37 : where K h is K h 0 or K h app , Δ A is the absorbance intensity change observed at each HSA concentration, Δ A max is the maximum absorbance intensity change under saturating HSA conditions, and n is the Hill coefficient.…”

Serum albumin and nucleic acids biodistribution: From molecular aspects to biotechnological applications

“…40,99 HSA also regulates the oncotic pressure and the fluid distribution between the body compartments, possibly providing the modification of ligands, rendering potential toxins harmless, affecting the pharmacokinetics of many drugs, and displaying anti-oxidant and (pseudo-) enzymatic properties. 7,14,23,33,34,40,70,76,99,122,132,146 HSA is composed by 585 amino acids and has a molecular weight of $67 kDa. It contains 35 Cys residues that form 17 disulfide bridges; Cys34 is the only solvent-exposed sulfhydryl residue playing a key role in the protein antioxidant activity.…”

“…Human SA (HSA) is the most abundant plasma protein (the serum concentration ranging between 35 and 50 g/L) and represents the main carrier of fatty acids (FAs) as well as of a wide range of endogenous and exogenous compounds, thus improving their solubility and half‐life 40,99 . HSA also regulates the oncotic pressure and the fluid distribution between the body compartments, possibly providing the modification of ligands, rendering potential toxins harmless, affecting the pharmacokinetics of many drugs, and displaying anti‐oxidant and (pseudo‐)enzymatic properties 7,14,23,33,34,40,70,76,99,122,132,146 …”