Evaluation of the Toxicity Potential of the Metabolites of Di-Isononyl Phthalate and of Their Interactions with Members of Family 1 of Sulfotransferases-A Computational Study

Abstract

Di-isononyl phthalates are chemicals that are widely used as plasticizers. Humans are extensively exposed to these compounds by dietary intake, through inhalation and skin absorption. Sulfotransferases (SULTs) are enzymes responsible for the detoxification and elimination of numerous endogenous and exogenous molecules from the body. Consequently, SULTs are involved in regulating the biological activity of various hormones and neurotransmitters. The present study considers a computational approach to predict the toxicological potential of the metabolites of di-isononyl phthalate. Furthermore, molecular docking was considered to evaluate the inhibitory potential of these metabolites against the members of family 1 of SULTs. The metabolites of di-isononyl phthalate reveal a potency to cause liver damage and to inhibit receptors activated by peroxisome proliferators. These metabolites are also usually able to inhibit the activity of the members of family 1 of SULTs, except for SULT1A3 and SULT1B1. The outcomes of this study are important for an enhanced understanding of the risk of human exposure to di-isononyl phthalates.

Keywords: di-isononyl phthalate monoesters; metabolism; molecular docking; toxicological effects.

Figure 1

Molecular lipophilicity potential on the molecular surface for the metabolites of di-isononyl phthalate and for the ligands that are present in the crystallographic structures of SULT1 enzymes. The hydrophobic parts of the surface are colored by violet and blue and the hydrophilic ones by orange and red.

Figure 2

Binding of mono-carboxy-isooctyl phthalate (orange sticks) and of mono-isononyl phthalate (cyan sticks) to the active site of SULT1A1*1. The binding poses correspond to the binding position of p-nitrophenol (yellow mesh surface) to SULT1A1*2 and superimposed on the structure of SULT1A1*1. The inactive cofactor adenosine-3′-5′-diphosphate that is present in the structural file of SULT1A1*1 is revealed in green sticks.

Figure 3

Binding of mono-isononyl phthalate (red sticks) and of mono-oxo-isononyl phthalate (blue sticks) to the active site of SULT1A1*2. The binding poses correspond to the binding position of p-nitrophenol (yellow mesh surface). The inactive cofactor adenosine-3′-5′-diphosphate is revealed in green sticks.

Figure 4

Binding of mono-carboxy-isononyl phthalate (orange sticks), of mono-hidroxy-isononyl phthalate (cyan sticks), of mono-isononyl phthalate (blue sticks) and of mono-oxo-isononyl phthalate (red sticks) to the active site of SULT1A1*3. All the binding poses correspond to the binding position of p-nitrophenol (yellow mesh surface). The inactive cofactor adenosine-3′-5′-diphosphate is revealed in green sticks.

Figure 5

Binding of mono-carboxy-isononyl phthalate (orange sticks), of mono-isononyl phthalate (cyan sticks) and of mono-oxo-isononyl phthalate (blue sticks) to the active site of SULT1A2. All the binding poses correspond to the binding position of p-nitrophenol (yellow mesh surface) to SULT1A1*2. The inactive cofactor adenosine-3′-5′-diphosphate is revealed in green sticks.

Figure 6

Binding of mono-carboxy-isononyl phthalate (orange sticks), of mono-hidroxy-isononyl phthalate (cyan sticks), of mono-isononyl phthalate (blue sticks) and of mono-oxo-isononyl phthalate (red sticks) to the active site of SULT1C1. All the binding poses correspond to the binding position of iodothyronine (yellow mesh surface). The inactive cofactor adenosine-3′-5′-diphosphate is revealed in green sticks.

Figure 7

Binding of mono-carboxy-isononyl phthalate (orange sticks), of mono-hidroxy-isononyl phthalate (cyan sticks), of mono-isononyl phthalate (blue sticks) and of mono-oxo-isononyl phthalate (red sticks) to the active site of SULT1A1E1. All the binding poses correspond to the binding position of 3,3′,5,5′-tetrachloro-4,4′-biphenyldiol (yellow mesh surface). The inactive cofactor adenosine-3′-5′-diphosphate is revealed in green sticks.

Figure 8

Three-dimensional structures of the di-isononyl phthalate and of its metabolites. The atoms are coloured like this: carbon—brown, oxygen—red, hydrogen—white.