Evidence of a strong interaction of 2,4-dichlorophenoxyacetic acid herbicide with human serum albumin

doi:10.1016/S0024-3205(98)00523-2

Life Sciences

Volume 63, Issue 26, 20 November 1998, Pages 2343-2351

https://doi.org/10.1016/S0024-3205(98)00523-2 Get rights and content

Abstract

The interaction of 2,4-dichlorophenoxyacetic acid herbicide (2,4-D) with human serum albumin (HSA) was studied using fluorescence and differential scanning calorimetry (DSC). Fluorescence displacement of 1-anilino-8-naphtalenesulfonate (ANS) bound to HSA was used to evaluate the binding affinity of 2,4-D to HSA. The binding is associated to a high affinity site of HSA located in the IIIA subdomain. The association constant (K_ass) of the herbicide was about 5 μM⁻¹, several times higher than the affinity found for pharmaceutical compounds. This relatively strong interaction with HSA was evidenced by the increase in HSA protein thermostability induced as consequence of herbicide interaction. 2,4-D induces an increase in the midpoint of thermal denaturation temperature from 60.1 °C in herbicide free solution to 75.6 °C in full ligand saturating condition. The calorimetric enthalpy and the excess heat capacity also increased upon 2,4-D binding. To investigate the possibility of other/s system/s of 2,4-D transport in blood, besides of HSA, the interaction of the herbicide with lipid monolayers was explored. No interaction was detected with any of the lipids tested. The overall results provided evidence that high affinity 2,4-D-HSA complex exhibits enhanced thermal stability and that HSA is the unique transport system for 2,4-D in blood.

References (43)

P.M. Newberne
Food Chem. Toxicol.
(1989)
R. Duffard et al.
Toxicology
(1982)
R. Duffard et al.
Neurotoxic. and Teratology
(1996)
H.A. Elo et al.
Toxicol. Appl. Pharmacol.
(1979)
M. Suwalsky et al.
Biochimica et Biophysica Acta
(1996)
J. Orberg
Acta. Pharmacol. Toxicol.
(1980)
J.B. Pritchard
J. Toxicol. Exper. Therap.
(1980)
H. Elo et al.
Comp. Biochem. Physiol.
(1988)
H. Hervonen et al.
Toxicol. Appl. Pharmacol.
(1982)
L. Bagatolli et al.
Journal of Pharmaceutical Sciences
(1996)

B. Maggio et al.

Biochem. J.

(1978)

K.S. Birdi

Lipid And Biopolymer Monolayer At Liquid Interfaces

(1989)

G.D. Fidelio et al.

Anal. Asoc. Quim. Arg.

(1986)

M.Asun Requero et al.

FEBS Lett.

(1995)

X.M. He et al.

Nature

(1992)

R.N. Chehin et al.

J. Membrane Biol.

(1995)

G. Bage et al.

Acta Pharmac. Tox.

(1973)

R. Duffard et al.

Acta Phisiolog. Latinoam.

(1981)

R. Duffard et al.

Neurochem. Res.

(1987)

G.Mori De Moro et al.

Neurochem. Res.

(1993)

A.W. Dudley et al.

Arch Pathol.

(1972)

Cited by (39)

Cell signaling mechanisms in developmental neurotoxicity
2022, Reproductive and Developmental Toxicology
The major mechanisms in cell signaling cascades by which neurotoxicants alter neural cell developmental processes during early life exposure are discussed in this chapter. It is important to note that many industrial chemicals, pesticides, and heavy metals are capable of inducing neurotoxicity in the human central nervous system (CNS), particularly in developing brains. Alterations in cell signaling pathways, perturbations of the genomic structure, and disruption of the communication process following exposure to neurotoxic compounds are known to cause transient or even permanent cellular functional impairments and are expected to lead to cell damage or cell death. The cell signaling mechanisms associated with developmental neurotoxicology are not well understood. A detailed understanding of the intricate cell signaling pathways pertaining to developmental neurotoxicity will provide new opportunities for development of rationale-based therapeutic strategies to treat various developmental disorders associated with environmental neurotoxicant exposure.
Serum profiling of anorexia nervosa: A <sup>1</sup>H NMR-based metabolomics study
2021, European Neuropsychopharmacology
Our understanding of pathophysiological mechanisms underlying anorexia nervosa (AN) is incomplete. The aim was to conduct a metabolomics profiling of serum samples from women with AN (n = 65), women who have recovered from AN (AN-REC, n = 65), and age-matched healthy female controls (HC, n = 65). Serum concentrations of 21 metabolites were measured using proton nuclear magnetic resonance (¹H NMR). We used orthogonal partial least-squares discriminant analysis (OPLS-DA) modeling to assign group classification based on the metabolites. Analysis of variance (ANOVA) was used to test for metabolite concentration differences across groups. The OPLS-DA model could distinguish between the AN and HC groups (p = 9.05 × 10–11 R2Y = 0.36, Q2 = 0.37) and between the AN-REC and HC groups (p = 8.47 × 10–6, R2Y = 0.36, Q2 = 0.24,), but not between the AN and AN-REC groups (p = 0.63). Lower methanol concentration in the AN and AN-REC group explained most of the variance. Likewise, the strongest finding in the univariate analyses was lower serum methanol concentration in both AN and AN-REC compared with HC, which withstood adjustment for body mass index (BMI). We report for the first time lower serum concentrations of methanol in AN. The fact that low methanol was also found in recovered AN suggests that low serum concentration of methanol could either be trait marker or a scar effect of AN.
Comparison of sample preparation approaches and validation of an extraction method for nitrosatable pesticides and metabolites in human serum and urine analyzed by liquid chromatography – Orbital ion trap mass spectrometry
2019, Journal of Chromatography A
Citation Excerpt :
For MCPA, analyte loss may be due to serum protein-binding. Chlorophenoxy herbicides, such as MCPA, bind extensively to albumin [27,28]. A study involving intentional self-poisoning with MCPA showed that the acidic pesticide bears protein-binding sites, one with an extremely high affinity [29].
In the acidic environment of the stomach, nitrosatable pesticide residues may react with nitrite to form potentially carcinogenic pesticide-associated N-nitroso compounds (PANOCs). The objective of this study was to develop a method for the analysis of 10 nitrosatable pesticides and breakdown products in human serum and urine. Three sample preparation methods were evaluated for extraction of target analytes from the biomatrices. Deproteinization by methanol for 300-μL aliquots of serum with a final extract volume of 225 μL resulted in excessive ion enhancement of some analytes and suppression of others. Three types of solid-phase extraction cartridges were tested for optimal analyte retention from 200-μL aliquots of serum with a final extract volume of 400 μL; this approach resulted in significant analyte loss for some compounds. The Quick, Easy, Cheap, Effective, Rugged, and Safe approach resulted in a suitable method for extraction of the analytes from each biomatrix. Biofluid samples (500 μL) were spiked to 100 μg L⁻¹ with analytical standards and extracted using 500 μL of acetonitrile (ACN) with 4% acetic acid (AcOH) for serum and 0.1% AcOH in ACN for urine. For extraction, 200 mg magnesium sulfate (MgSO₄) and 50 mg sodium acetate were added for serum and 200 mg MgSO₄ and 50 mg sodium chloride were added for urine. Final extract volumes for both biomatrices using the QuEChERS method was 400 μL after dilution. Samples were analyzed via ultra-high pressure liquid chromatography/high-resolution accurate mass orbital ion trap mass spectrometry. Mean recoveries for target analytes in serum and urine ranged between 74 and 120% (%RSD < 12) and 96 to 116% (%RSD ≤ 10), respectively. These methods may be used in large-scale biomonitoring studies to analyze PANNs and their parent compounds in human serum and urine.
Transport of 2,4-dichloro phenoxyacetic acid by human Na <sup>+</sup> -coupled monocarboxylate transporter 1 (hSMCT1, SLC5A8)
2019, Drug Metabolism and Pharmacokinetics
Citation Excerpt :
2,4-D is excreted in urine without any change (more than 80% of dose). 2,4-D in the serum is bound extensively to serum proteins (unbound fraction, 0.12) [6,51]. Accordingly, the glomerular filtration might be an approximately half contribution to the overall renal clearance (approximate 1.4 l/h) [3,5,6].
Using X. laevis oocyte expression system, we investigated whether human Na⁺-coupled monocarboxylate transporter 1 (SLC5A8, hSMCT1) is involved in 2,4-dichlorophenoxyacetate (2,4-D) uptake by the renal tubular epithelial cells. 2,4-D is a herbicide that causes nephrotoxicity. Heterologous expression of hSMCT1 in X. laevis oocytes conferred the ability to take up 2,4-D; the induced uptake process was Na⁺-dependent and electrogenic. The Na⁺-dependent uptake of 2,4-D was inhibited not only by known hSMCT1 substrates, but also by many structural analogs of 2,4-D. The currents induced by 2,4-D, 4-chlorophenoxyacetate (4-CPA) and 2-methyl-4-chlorophenoxyacetate (MCPA) were saturable: the rank order of the maximal induced current and the affinity for hSMCT1was 2,4-D > 4-CPA > MCPA. The relationship between the structures of the derivatives and their transport activity implied specific structural features in a compound for recognition as a substrate by hSMCT1. Furthermore, we have demonstrated using purified rabbit renal brush-border membrane vesicles that 2,4-D potently inhibited the Na⁺-dependent uptake of pyroglutamate, a typical substrate for Smct1, and that 2,4-D uptake process was Na⁺-dependent, saturable and inhibitable by a potent blocker, ibuprofen. We conclude that hSMCT1 is involved partially in the renal reabsorption of 2,4-D and its derivatives and their nephrotoxicity.
Structural, spectral, DFT and biological studies on macrocyclic mononuclear ruthenium (II) complexes
2017, Journal of Molecular Structure
Citation Excerpt :
The optimized molecular Structure, bond length, bond angle, dihedral angle and chemical reactivity L1H, L2H & L3H have been established using DFT method. In order to explain the co-ordination of C=N group, the IR spectra of free ligand were compared with newly synthesized ruthenium (II) complexes, where L1H, L2H, & L3H exhibited intense bands at 1647 cm−1, 1645 cm−1 and 1650 cm−1, respectively [21–23]. However the complexes showed sharp bands at 1604 cm−1, 1600 cm−1 and 1600 cm−1 which corresponding to the azomethine.
Macrocyclic mononuclear ruthenium (II) complexes have been synthesized by condensation method [Ru (L1, L2, L3) Cl₂] L₁ = (C₃₆ H₃₁ N₉), L₂= (C₄₂H₃₆N₈), L₃= (C₃₂H₃₂ N₈)]. These ruthenium complexes have been established by elemental analyses and spectroscopic techniques (Fourier transform infrared spectroscopy (FT-IR), ¹H- nuclear magnetic resonance (NMR), ¹³C- NMR and Electrospray ionization mass spectrometry (ESI-MS)). The coordination mode of the ligand has been confirmed and the octahedral geometry around the ruthenium ion has been revealed. Binding affinity and binding mode of ruthenium (II) complexes with Bovine serum Albumin (BSA) have been characterized by Emission spectra analysis. UV–Visible and fluorescence spectroscopic techniques have also been utilized to examine the interaction between ligand and its complexes L1, L2, & L3 with BSA. Chemical parameters and molecular structure of Ru (II) complexes L1H, L2H, & L3H have been determined by DFT coupled with B3LYP/6-311G** functional in both the gaseous and aqueous phases.
Cell signaling mechanisms in developmental neurotoxicity
2017, Reproductive and Developmental Toxicology
The major mechanisms in cell signaling cascades by which neurotoxicants alter neural cell developmental processes during early life exposure are discussed in this chapter. It is important to note that many industrial chemicals, pesticides, and heavy metals are capable of inducing neurotoxicity in the human central nervous system (CNS), particularly in developing brains. Alterations in cell signaling pathways, perturbations of the genomic structure, and disruption of the communication process following exposure to neurotoxic compounds are known to cause transient or even permanent cellular functional impairments and are expected to lead to cell damage or cell death. The cell signaling mechanisms associated with developmental neurotoxicology are not well understood. A detailed understanding of the intricate cell signaling pathways pertaining to developmental neurotoxicity will provide new opportunities for development of rationale-based therapeutic strategies to treat various developmental disorders associated with environmental neurotoxicant exposure.

View all citing articles on Scopus

View full text

Evidence of a strong interaction of 2,4-dichlorophenoxyacetic acid herbicide with human serum albumin

Abstract

Food Chem. Toxicol.

Toxicology

Neurotoxic. and Teratology

Toxicol. Appl. Pharmacol.

Biochimica et Biophysica Acta

Acta. Pharmacol. Toxicol.

J. Toxicol. Exper. Therap.

Comp. Biochem. Physiol.

Toxicol. Appl. Pharmacol.

Journal of Pharmaceutical Sciences

Biochem. J.

Anal. Asoc. Quim. Arg.

FEBS Lett.

Nature

J. Membrane Biol.

Acta Pharmac. Tox.

Acta Phisiolog. Latinoam.

Neurochem. Res.

Neurochem. Res.

Arch Pathol.