Chemical Protectors against the Toxic Effects of Paracetamol

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Article Cite This: ACS Omega 2018, 3, 18582−18591

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Chemical Protectors against the Toxic Effects of Paracetamol (Acetaminophen) and Its Meta Analogue: Preventing Protein Arylation Romina Castañeda-Arriaga,† Adriana Pérez-González,‡ and Annia Galano*,† †

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Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Col. Vicentina, Iztapalapa, C. P., 09340 México D. F., Mexico ‡ CONACYTUniversidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Col. Vicentina. Iztapalapa, C. P., 09340 México D. F., Mexico S Supporting Information *

ABSTRACT: The potential role of nine thiols as chemical protectors against the toxicity of paracetamol (acetaminophen, APAP) and its meta analogue N-acetyl-m-aminophenol (AMAP) was investigated using the density functional theory. They are glutathione (GSH), N-acetylcysteine (NAC), NAC amide (NACA), tiopronine (TPR), dihydrolipoic acid (DHL), 6-mercaptopurine (6MP), 6-thioguanine (6TG), 2,3-dimercaprol (DMC), and D-penicillamine (PNA). The investigation was focused on the toxic effects derived from protein arylation at cysteine residues, induced by the quinone imines formed from APAP and AMAP. On the basis of both thermochemical and kinetic considerations, with the exceptions of 6MP and 6TG, the investigated thiols may be useful in protecting the chemical integrity of cysteine residues in proteins from arylation by quinone imines. The order of efficiency for that purpose is predicted to be NAC > GSH > TPR > NACA > DMC > DHL. However, considering physicochemical properties that may affect bioavailability and cell permeability, DHL seems to be the best prospect to be orally supplied.

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INTRODUCTION N-Acetyl-p-aminophenol (i.e., paracetamol, acetaminophen, or APAP; Scheme 1), is a widely used analgesic and antipyretic.

Scheme 2. Structure of NAPQI, PBQI, and Related Species, with Site Numbering

Scheme 1. Structures of Paracetamol (APAP), Its Meta Analogue (AMAP)

Although safe at therapeutic doses, APAP overdoses can be toxic. Such toxicity is considered the most frequent cause of drug-induced liver injuries1−3 and is also known to affect other organs.4−10 N-Acetyl-p-benzoquinone imine (NAPQI, Scheme 2) is a metabolite of APAP, which has been identified as responsible for the APAP hepatotoxicity.3,11 At APAP therapeutic doses, NAPQI is properly detoxified by glutathione (GSH). On the contrary, when APAP is consumed in excess, NAPQI accumulates and GSH is insufficient for preventing the © 2018 American Chemical Society

associated injuries.2,3,11,12 Chemically speaking, such injures are characterized by the formation of NAPQI adducts with the thiol group in cysteine residues, which eventually result in the Received: October 25, 2018 Accepted: December 13, 2018 Published: December 27, 2018 18582

DOI: 10.1021/acsomega.8b02943 ACS Omega 2018, 3, 18582−18591

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production of the oxidative species.13,14 The adduct formation mainly involves covalent bonding between the thiol group in cysteine residues and the ortho position, with respect to the keto group, in NAPQI.15 In addition, p-benzoquinone imine (PBQI, Scheme 2), which can be produced by deacetylation of NAPQI,16 has been proposed as a potential contributor to the APAP toxicity.17 The paracetamol meta analogue, N-acetyl-m-aminophenol (AMAP, Scheme 1), has been suggested as a safer alternative to APAP.18,19 However, there is also evidence indicating otherwise.15,20,21 AMAP metabolites (Scheme 2), the yield of which is similar to that of APAP, have also been found to form adducts with cysteine residues, by binding to the thiol group.15 Therefore, it seems that different approaches for preventing APAP (and AMAP) toxicity are required. Chemical protectors are likely candidates for that purpose. As previously mentioned, endogenously produced GSH is known to offer protection against the toxic effects of APAP. GSH is a tripeptide containing cysteine as the central residue (Scheme 3). Thus, its nonenzymatic protection involves its

amide group replacing the carboxyl group in NAC, which increases lipophilicity and facilitates crossing cell membranes. Therefore, lower doses of NACA (compared to NAC) are required to counteract APAP poisoning, which may prevent adverse side effects.52 Some studies in animal models have shown that NACA is more efficient than NAC against APAPinduced toxicity because of the higher bioavailability of NACA, although both have the same ways of action.53 In addition, NACA has been proved to have antioxidant effects, which are capable of scavenging ROS, and avoid oxidative stress.52,55 Thus, it is expected to prevent the damaging effects of the oxidative species arising from the APAP toxicity. The presence of the thiol group seems to be the key structural feature in APAP antidotes. This is logical because this group would bind to NAPQI preventing protein arylation at cysteine residues. In addition, thiols are usually good antioxidants known to efficiently deactivate ROS. Therefore, the potential role of several thiols as chemical protectors against the toxic effects of APAP and AMAP has been investigated in this work. To that purpose, protection mechanism (ii), that is, direct binding to NAPQI and analogues, has been considered. The corresponding thermochemical and kinetic data were compared with those of GSH, NACA, and NAC. On the basis of these comparisons, some of the investigated compounds are proposed as promising alternatives for the use of NAC in the treatment of APAP poisoning.

Scheme 3. Structures of the Thiol Investigated in This Work

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INVESTIGATED COMPOUNDS Nine thiols were chosen for this investigation (Scheme 3). They are tiopronine (TPR), dihydrolipoic acid (DHL), 6mercaptopurine (6MP), 6-thioguanine (6TG), 2,3-dimercaprol (DMC), D-penicillamine (PNA), NAC, NACA, and GSH. Although 6MP and 6TG have two tautomeric forms (Figure S1, Supporting Information), those included in the present investigation are the ones with the thiol group. As discussed in the Introduction section, NAC, NACA, and GSH are already known to counteract the toxic effects of APAP. To the best of our knowledge, the other investigated compounds have been used, so far, for other purposes. Among them, DHL is probably the most widely used thiol. Its therapeutic action has been frequently associated with its antioxidant properties, which involve free-radical scavenging and protein-repairing capabilities.56 It has been reported to offer neuroprotection, in vitro, against oxidative stress.57 It was also found that 1 month treatment with DHL helps mitigating the pain symptoms typical of several stress oxidative-dependent diseases.58 The antioxidant, antiinflammatory, and immunomodulatory activities of DHL have been identified as very helpful in preventing miscarriage and preterm delivery in pregnant women.59 Current studies support using DHL in the auxiliary treatment of many diseases including cancer, acquired immune deficiency syndrome, diabetes, hypertension, and inflammation as well as cardiovascular, autoimmune, hepatic, and neurodegenerative disorders.60−65 DHL improves neurofunction and alleviated inflammation in early brain injury, after subarachnoid hemorrhage.66 It also has inhibitory effects on the viability and proliferation of breast cancer cells.67 On the other hand, TPR has been used to treat cystinuria,68−70 rheumatoid arthritis,71−75 and liver damage.76,77 It also has antioxidant effects, as free-radical scavenger, metal chelator, and inhibitor of the formation of OH radicals via Fenton reactions.78,79 6MP has been found to be effective

role as a sacrifice target that forms adducts with NAPQI,22 preventing protein binding.23 It has been estimated that, in vivo, the formation of such adducts takes place at a rate of 3.4 × 104 M−1 s−1 nonenzymatically and at a rate of 2.0 × 107 M−1 s−1 when catalyzed by GSH S-transferases.24 In addition, GSH is well known for its antioxidant activity,25−33 which is expected to help counteracting the effects of the oxidative species34 formed as a consequence of the APAP toxicity. Other chemicals containing the thiol group have been tested, or used, as antidotes against APAP poisoning. Some of initially used chemicals in this context were cysteine, methionine, cysteamine, and N-acetylcysteine (NAC),35−38 the latter being the most widely used in this context. Several mechanisms have been proposed to contribute to the NAC protection against the hepatotoxicity of APAP: (i) by providing cysteine for GSH synthesis;39,40 (ii) by forming adducts with NAPQI;24,41 (iii) by reacting with reactive oxygen species (ROS);15 (iv) by reducing NAPQI back to APAP.24,42,43 However, some adverse effects have been associated with NAC administration as an antidote of APAP overdose including anaphylactoid reactions, nausea, vomiting, headache, and renal failure.44−51 In addition, because of its poor bioavailability (the carboxyl group deprotonates at physiological pH, making NAC negatively charged),52 high doses and/or long treatment times of NAC are required. NAC amide (NACA) has emerged as a promising alternative to NAC for treating APAP-induced toxicity.53,54 NACA has an 18583


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Table 1. Acid Constants, Expressed as pKa Values, of the Thiols Investigated in the Present Work; the Molar Fractions (Mf) of the Neutral (HnA), Monoanionic (Hn−1A−), and Dianionic (Hn−2A2−) Species at pH = 7.4 pKa1 NAC NACA TPR DHL GSH 6MP 6TG PNA DMC

b

3.11 9.12a 3.59b 4.85c 3.59b 2.25a 2.71a 1.90b 8.63b

pKa2

pKa3 b

9.58

8.87b 10.7c 8.75b 4.19a 5.05a 7.96b 10.65b

10.67b

M

f (HnA)

0.0001 0.9813 0.0001 0.0028 0.0001 0.0006 0.0040 0.7840 0.9444

M

f (Hn−1A−) 0.9934 0.0187 0.9671 0.9967 0.9571 0.9994 0.9960 0.2159 0.0556

M

f (Hn−2A2−) 0.0066 0.0328 0.0005 0.0428

0.0001 GSH > TPR > NACA > DMC > DHL. However, considering physicochemical properties that may affect bioavailability and cell permeability, DHL seems to be the best prospect to be orally supplied.

quinone imines is step 1, that is, the initial addition. It should be kept in mind, though, that pH influences step 3. Thus, this step might become endergonic under high acid conditions. Other Considerations. On the basis of both thermochemical and kinetic considerations, most of the investigated thiols were identified as promising candidates for protecting the chemical integrity of cysteine residues in proteins from arylation by quinone imines. The order of efficiency for that purpose would be NAC > GSH > TPR > NACA > DMC > DHL. However, there are other important factors to consider that may affect bioavailability and cell permeability. Therefore, several physicochemical parameters usually used as indicators for absorption, distribution, metabolism, and excretion (ADME) properties were estimated for all the investigated thiols. These parameters were chosen to check if the thiols satisfy Lipinski’s,116 Ghose’s,117 and Veber’s118 criteria and are reported in Table S13 (Supporting Information). As previously mentioned, the partition coefficient octanol/ water (log P) is considered problematic for NAC (log P = −2.44), which was one of the reasons of using NACA (log P = −0.94) instead. Considering Lipinski’s and Ghose’s rules together, the desired value of log P should range from −0.4 to 5.0. Among the thiols proposed as the best protectors against protein arylation, only DHL (log P = 2.01) and DMC (log P = 0.31) fulfill this requirement. The log P value for TPR (log P = −1.56) is between those of NAC and NACA, while that of GSH (log P = −4.97) is the one differing the most for the target values. Regarding the number of H bond acceptors (HBA), H bond donors (HBD), and rotatable bonds, all the investigated thiols are within the desirable ranges except for GSH, with HBA = 6. All the thiols comply with Lipinski’s rule for molecular weight (MW), although that of DMC (MW = 124.23) is to some extent below Ghose’s low threshold (160). Ghose’s rules for the number of nonhydrogen atoms (XAt) and molar refractivity (MR) are the ones for which most of the investigated thiols are outside the desirable ranges (20 ≤ XAt ≤ 70, 40 ≤ MR ≤ 130). They all have less than 20 XAt, with the exception of GSH. Their MR values are slightly lower than 40 for all of them but GSH and DHL. Thus, considering the ADME properties estimated here, DHL seems to be the best prospect to be orally supplied for preventing paracetamol toxicity associated with protein arylation. The other thiols might present bioavailability and/ or cell permeability issues. However, Lipinski’s, Ghose’s, and Veber’s criteria are only guiding rules, and they have been estimated here through structure−activity relationships. Therefore, this point should be further explored, preferably by experimental investigations.

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COMPUTATIONAL DETAILS Geometry optimizations and frequency calculations were performed within the framework of the density functional theory, with the Gaussian 09 package of programs.119 In particular, the M05-2X functional120 was chosen because it is recommended for kinetic calculations.120,121 It was used in conjunction with the 6-31+G(d,p) basis set and the solvation model based on density (SMD),122 using water as solvent to mimic aqueous environments. SMD is considered to be a universal solvation model, applicable to any charged or uncharged solute in any solvent or liquid medium.122 Local minima and saddle points were identified by the number of imaginary frequencies (0 and 1, respectively). Thermodynamic corrections at 298.15 K were included in the calculation of relative energies, which correspond to the 1 M standard state. The rate constants (k) were calculated using the same standard state and the conventional transition-state theory123−125 with harmonic vibrational frequencies and Eckart tunneling.126,127 Kinetic calculations were not performed for the endergonic reaction pathways because they are expected to be reversible to a significant extent. The abundance of acid− base species at physiological pH was considered in the calculation of the rate constants. The overall rate coefficients were obtained as the sum of the rate coefficients corresponding to the reaction pathways identified as viable. More details on how to apply this procedure can be found elsewhere.15,128 Calculated rate constants (k) close to the diffusion limit were corrected using the Collins−Kimball theory,129 the steady-state Smoluchowski rate constant for an irreversible bimolecular diffusion-controlled reaction,130 and the Stokes−Einstein131,132 approaches. This strategy has been previously validated.128 Acid constants, expressed as pKa, were calculated using the fitted parameters approach.133,134 It has been demonstrated that this approach produces deviations from experiments that are systematically lower than 0.5 pKa units, in terms of mean unsigned errors. This approach uses experimental pKa values to obtain two parameters (m and C0) from linear fittings, which are then used to calculate the pKa of the target molecule. The parameters used here have been previously proposed and validated.133

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CONCLUSIONS A previously proposed mechanism for the reactions between thiols and quinone imine was used to investigate the potential role of nine thiols as chemical protectors against the toxicity of paracetamol (acetaminophen) and its meta analogue. The investigated protection is intended to prevent protein arylation at cysteine residues. The first step (addition of quinone imines to the thiol group) was identified as the rate-determining step and the crucial one for the target reaction. It was found to involve only the deprotonate fractions (i.e., the thiolate anions). Thus, the pKa of the thiols, and their relationship with the pH of the environment, are expected to influence the efficiency of thiols

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b02943. Gibbs free energies and activation energies of all the investigated reaction steps, ADME properties of the investigated thiols, structures of 6MP and 6TG 18587


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tautomers, and optimized structures of the transition states (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected], [email protected]. ORCID

Annia Galano: 0000-0002-1470-3060 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the Laboratorio de Visualización y Cómputo Paralelo at Universidad Autónoma MetropolitanaIztapalapa. A.P.-G. Acknowledges the economic support of the Program of CátedrasCONACYT from CONACyTUAMI (2015−2025), ID-Investigador 435. R.C.-A. acknowledges the financial support through a CONACyT postdoctoral fellowship, through project IFC-2016/1828.

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