AVERTING CANCER EFFECT OF PARACETAMOL AND PHENACETIN BY N-ACETYLCYSTEINE AND ITS ANALOGUESHTML Full Text
AVERTING CANCER EFFECT OF PARACETAMOL AND PHENACETIN BY N-ACETYLCYSTEINE AND ITS ANALOGUES
Anwar El-Shahawy *, Nagwa Abo El-Maali and Hassan H. El-Hawary
Department of Chemistry, Faculty of Science, Assiut University 71516, Egypt.
ABSTRACT: Comparative DFT calculations have been studied for Paracetamol (PA) and its analog Phenacetin (PH) to verify their electronic resemblance. DFT studies concluded that PA and PH have the lower energy predominant trans conformers with respect the cis-conformers. From TD-DFT studies, the electronic transition energies between the ground state and singlet excited states for the two conformers have been done. The metabolized product of PA or PH, i.e., m-PA in the liver of the human being is N-acetylimidoquinone. The electron affinity, Ea, of metabolized Paracetamol (m-PA) is sufficient to interact with the nucleic acid bases in the liver. So long as the m-PA product is produced in the liver and the electron transfer energy, Eet, between m-PA and nucleic acid bases has very small energy value with guanine, i.e., 0.382 eV, from the nucleus of the cell in the liver producing a spontaneous electron transfer from the nucleus to m-PA producing cationic nucleus leading to the carcinogenic behavior of the cell in the liver. The presence of glutathione in the liver prevents the formation of m-PA via proton transfer, avoiding the carcinogenic effect of PA and PH. Repetitive usage of PA or PH drug consumes the glutathione in the liver, permitting the interaction between m-PA and guanine in the liver. Addition of N-acetylcysteine (NAC), N-acetylmethionine (NAM) or N-acetylglucoseamine (NAGA) prevents the formation of m-PA, i.e., cancer effect. Therefore PA and PH can be used as safe drugs after mixing with the pharmacological dose of N-acetylcysteine, N-acetylmethionine or N-Acetylglucoseamine.
DFT, TD-DFT, PA, PH, NAC, NAM,NAGA, Eet
INTRODUCTION: Paracetamol instead of Phenacetin is worldwide use as analgesic, and antipyretic drug 1 not as anti-inflammatory and literature including 93 references reported the clinical side effects of Paracetamol in terms of the following system processes: allergic and skin; hematol; renal diseases; pregnant lactation; cancer effect 2. Availability effect of EtOH with PA was studied by Wojcicki et al., 3 in healthy man.
Goto et al., had studied the charge transfer energy values for some pyridines and pyrimidines by CNDO/2 4.
Charge transfer complex formation between nucleic acid bases and isoproterenol has been studied using UV spectrophotometer measurement by Taha et al. 5 Tautomeric structures of uracil and its electrochemical corrosion behavior of mild steel in the acidic medium were studied using CNDO calculations by Makhlouf and El-Shahawy 6. The interaction of hydrogen bonding studies in drug-receptor has been performed by Ghafourian et al. 7 Severe hepatotoxicity and nephrotoxicity as a reason for the accumulation of toxic metabolites of Paracetamol were studied by Moffat 8. The CT-complex formation between cytoseine, thymine adenine, and uracil with catechol in acidic medium has been studied by Al-Obeidi et al. 9 The formation of charge transfer complex between oxytetracycline and tetracycline with purines, pyrimidines, and amino acids was studied by Lahiri 10. El-Shahawy et al., have studied the formation of CT- complex between 4, 4'-dimethoxydiquinone with uracil using CNDO calculations 11. Paracetamol toxicity is manifested primarily in the liver. Hepatic damage from PA can be treated with N-Acetylcysteine (NAC) if started within 10 h from ingestion 12.
The rheumatism therapy has been known since many years ago with the usage of extracts of plants such as willow bark or leaves, most of which contain salicylates. Bayer Company in Germany made the acetylsalicylate form salicylic acid in 1897. This drug has been named ‘‘Aspirin’’ and became the most worldwide use medicine of all time. In 1971, Vane found out the mechanism by which aspirin makes its anti-inflammatory, analgesic and antipyretic effects
He proved that aspirin and other non-steroid anti-inflammatory drugs (NSAIDs) prevent the enzyme activity which is now called cyclooxygenase (COX) producing prostaglandins (PGs) that cause inflammation, swelling, pain, and fever. However, by inhibiting this key enzyme in PG synthesis, the aspirin-like drugs also prevented the production of physiologically important PGs which save the mucosa of the stomach from damage by HCl.
This conclusion provided an explanation for the therapeutic actions and accompanied side effects of the aspirin-like drugs. Twenty years later, with the discovery of a second COX gene, it was clear that there are two forms of the COX enzyme. The constitutive form, COX-1 which supports the beneficial homeostatic functions, whereas the second inducible form, COX-2, is unregulated by inflammatory mediators and its products lead to many of the symptoms of inflammatory diseases such as rheumatoid and osteoarthritis 13.
Materials: Paracetamol (Chem. Pharm. Works, Dupnitsa) was recrystallized from water to show a melting point of 168°. The ethyl alcohol solvent was extra pure Prolabo and Merk grades.
Instrumentation: The UV-visible spectra of some of the studied compounds had been scanned by UV-2101 PC UV-vis scanning spectrophotometer Shimadzu.
The temperature effect on the PA spectrum has been scanned by Perkin Elmer Lambda 35 UV/V is spectrophotometer USA.
Method of Calculations:
Computational Studies: Computational study on an isolated gaseous molecule was done by the aid of DFT-method. Minimizing structures energies have been achieved using B3LYP with 6-31**G basis set.
Calculations were performed on the minimum energy structures using the closed shell Hartree-Fock, Becke's three parameters density functional theory, DFT, 14 in combination with the Lee, Yang and Parr correlation functional B3LYP 15 with basis set 6-31**G. The differentiation between the conformers' cis and trans was based on the total energy difference which has been calculated via SCF using RHF for these types of molecules and UHF for the molecular ions (cations and anions).
With respect to DFT calculations, it has been performed as B3LYP/6-31**G and the energy of the density function theory can be represented as follows 16, 17.
Where is the electron density.
Where Ci is the eigenvectors and
Where is the Hamiltonian of the total energy.
Electron Transfer Studies: The electron transfer energy in the CT–complex between the donor and the acceptor (cation and anion) was calculated according to the following equation 18.
Where ID is the ionization potential of the donor and EA is the electron affinity of the acceptor. C+ is the columbic potential energy of the donor as a cation, and C- is the columbic potential energy of the acceptor as an anion. The columbic potential energy can be calculated, according to the following equation 18.
Where Zi and Zj are the charge densities and rij is the distance between two atoms in the molecule of N atoms. The ET-band position in nm can be obtained by dividing 1240.824 by the electron transfer energy in electron volts.
λ × E = 1.241 × 103 nm eV
RESULT AND DISCUSSIONS:
Conformational Studies: Also, it is necessary to compare the conformers of PA with its analog PH. The cis-conformer is the structure in which the amino hydrogen atom and the carbonyl group are on the same side.
TABLE 1: DFT (B3LYP/6-31**G) PARAMETERS OF THE STUDIED COMPOUNDS
|Compound||TE au||Ip ev||Ea ev|
TE is the total energy in au unit.
Ip is the ionization energy in eV unit.
Ea is the electron affinity in eV unit
The trans-conformer is the structure in which the amino hydrogen atom and the carbonyl group are in opposite sides, Fig. 1.
FIG. 1: THE CONFORMERS OF X= OH OR OEt
The existence of conformers cis and trans, Fig. 1, is probably due to the small energy difference between them in Paracetamol and Phenacetin. The ratio of the existence of the two conformers depends on the energy difference between them and the temperature, 27 ºC, according to Boltzmann equation 19.
TABLE 2: B3LYP/6-31**G ENERGY DIFFERENCE BETWEEN THE CONFORMERS AT 27 o
|Compound||Δ E eV||N/N0||N|
|PH cis/trans||0.27211||2.67x 10-5||106135x1019|
Δ E is the energy difference between the two conformers.
N/No is the ratio between the two conformers.
N is the number of the cis-conformer molecules of the higher energy in one mole.
From the previous Table 2, it is clear that the trans-conformer has the lower energy in PA as the situation in PH molecules abundance. The energy difference between the two conformers is a fraction of electron volt; therefore their abundance is probably in the normal temperature, especially the transforms.
Regarding the existence of the two conformers in the room temperature in solutions 20, it is probable to change the temperature of the UV-spectra of PA solution in ethyl alcohol, Fig. 2, to find out duplicity relative intensity change in the UV-band at different temperatures.
In realty, there isn’t observable duplicity at the top of the UV-band of PA, and hence there isn’t any change in the relative intensity change indicating to the absence of the conformers. Using TD-DFT calculations, the electronic spectra have been studied for both conformers cis and trans, to find out the electronic transitions between the ground state and the excited singlet states as follows in the following Table 3 and 4.
TABLE 3: ELECTRONIC TRANSITION ENERGIES BETWEEN THE GROUND STATE AND THE SINGLET EXCITED STATES OF TRANS-PARACETAMOL
|Excited State 1:||Singlet-A|
|40 -> 42||0.69844||4.5698 eV 271.31 nm f=0.0001|
|Excited State 2:||Singlet-A|
|38 -> 41||0.23477||4.6453 eV 266.90 nm f=0.0428|
|38 -> 46||-0.11219|
|40 -> 41||0.18160|
|40 -> 43||0.61001|
|Excited State 1:||Singlet-A|
|40 -> 44||0.70111||4.7303 eV 262.11 nm f=0.0001|
TABLE 4: ELECTRONIC TRANSITION ENERGIES BETWEEN THE GROUND STATE AND THE SINGLET EXCITED STATES OF CIS-PARACETAMOL
|Excited State 1:||Singlet-A|
|38 -> 42||0.21497||4.5836 eV 270.49 nm f=0.0442|
|40 -> 41||0.63233|
|40 -> 42||-0.13652|
|Excited State 2:||Singlet-A|
|40 -> 42||0.18779||4.7849 eV 259.11 nm f=0.0033|
|40 -> 43||0.66942|
|Excited State 3:||Singlet-A|
|39 -> 41||-0.18640|
|39 -> 42||-0.40338|
|39 -> 45||0.10294|
|39 -> 46||-0.19266|
|40 -> 42||0.38604|
|40 -> 43||-0.16222l|
f is the oscillator strength.
From the previous Table 3 and 4, it is clear that the allowed transition energies for cis and trans conformers lie at 254nm and 267nm respectively which they are very near to each other, then the expected duplicity can’t be observed by the temperature effect at 248 nm in the UV spectrum in ethyl alcohol 21 as shown in the following Fig. 2.
The experimental λ max of Paracetamol lies at 261 nm in chloroform solvent21 over broadband including the λ max at positions 254 nm and 267 nm for cis and trans conformers respectively.
FIG. 2: THE HEAT EFFECT ON THE ELECTRONIC SPECTRUM OF PA MOLECULE IN EtOH. (a) at (45 ºC), (b) at (35 ºC), (c) at (25 ºC), (d) at (15 ºC)
Electron Transfer Studies: PA and PH are metabolized primarily in the liver 22-24, into toxic and non-toxic products Fig. 3, 4, and 9. Three metabolic pathways are notable, Fig. 4, and 9. The hepatic enzyme system metabolizes Paracetamol, producing the toxic product as N-acetylimidoquinone, which has the symbol (m-PA) for simplicity, Fig. 4.
FIG. 3: METABOLIZED PRODUCT, m-PA FROM PA, AND pH
All three pathways yield final products that are inactive, non-toxic, and eventually excreted by the kidneys. The intermediate product m-PA is also produced via the metabolism of PH in the liver, Fig. 3 and 4. This means that m-PA is primarily responsible for the toxic effects of PA and PH. Then it is interesting to use quantum mechanical DFT (B3LYP/6-31**G) calculations to study the interaction between this product, m-PA, and the nucleic acid bases in the nucleus in the liver cell.
FIG. 4: SCHEME OF METABOLISM OF PA AND pH TO FORM m PA
These studies deal with the electron transfer energy of the metabolized product, m-PA with the nucleic acid bases (NAB), Fig. 5, in the liver, to acquire the liver cell the carcinogenic nature via the electron transfer between them. The electron transfer energy depends mainly on the ionization potential of the donor, the electron affinity of the acceptor, and the columbic potential energies of the cation of the donor, and the anion of the acceptor. The ionization potential and the electron affinity were calculated via DFT/B3LYP-6-31**G method for these molecules and their ions. Also, the columbic potential energies of the cation (donor) and the anion (acceptor) were calculated using the Cartesian coordinates of the optimized molecular ions and the Mulliken charge densities of the molecular ions using the output data coming out from the DFT method using the equation 2 in the 3.2-electron transfer section.
FIG. 5: NUCLEIC ACID BASES (NAB)
The acceptor and the donor can be defined by the relative values of the ionization potential energy and the electron affinity of the two interacting molecules. The molecule having higher electron affinity and high ionization potential acts as an acceptor to form an anion in the ct-complex. The molecule has lower electron affinity, and lower potential ionization acts as a donor to form a cation in the ct-complex.
Since the electron affinities of PA and PH are lower than those of nucleic acid bases, Table 1, therefore they act as a donor to produce charge transfer complex in which these molecules are cationic and the nucleic acid bases are anionic. In contrary, the metabolized product, m-PA, has much higher electron affinity than those of the nucleic acid bases, Table 1, therefore m-PA is anionic, and the nucleic acid bases are cationic in the ct-complex.
After calculation of the columbic potential energies of PA, PH, and m-PA with the nucleic acid bases using equation 2 in the 3.2-electron transfer section, the total columbic potential energies with the nucleic acid bases have been obtained in the following Table 5.
TABLE 5: THE COLUMBIC POTENTIAL ENERGIES (C= C+ + C-) of PA, PH, and m-PA WITH THE NUCLEIC ACID BASES IN eV
|Compound||C, eV adenine||C eV guanine||C eV, cytosine||C eV, uracil|
Using the ionization potential energies, the electron affinities of the studied molecules from Table 1 and the columbic potential energies from the previous Table 5, to calculate the electron transfer energies which can be illustrated as cancer energy barrier. When it has a small value, it means the electron transfer being easy to produce the carcinogenic effect.
In contrary, the high value of the cancer energy barrier indicates to the arduousness of the electron transfer to render the drug being safe from the cancer effect. The values of the cancer energy barriers Eet of the studied compounds have been obtained in the following Table 6.
FIG. 6: THE OPTIMIZED STRUCTURES OF NAC, GSH, AND m-PA.
TABLE 7: DFT/B3LYP-6-31G** CHARGE DENSITIES OF GSH, NAC AND m-PA MOLECULES
|N.A.B||m-PA Eet eV||Ph.ci Eet eV.||Ph.tr Eet eV||Pa cis Eet eV||Pa.tr Eet eV|
TABLE 8: THE CHARGE DENSITIES OF THE FREE RADICALS OF NAC AND m-PA
|1||N -0.057143||C -1.003289||C 0.285352|
|2||C -0.615967||S0.397550||C 0.492989|
|3||C -0.196757||N -0.206871||C -0.84676|
|4||C -0.373881||C 0.540236||C -0.45967|
|5||O -0.456866||O -0.465326||C-0.24005|
|6||C 0.355514||C -0.746486||C 0.182835|
|7||O -0.402651||C 0.338204||N -0.10934|
|8||O -0.482321||C -0.820600||C 0.652457|
|9||C -1.163754||O -0.388053||C -0.919709|
|10||S 0.383267||H 0.335015||O -0.413230|
|11||N -0.190125||H 0.068367||O -0.451106|
|12||C -0.140436||H 0.462384||H 0.316077|
|13||O -0.421302||H 0.244840||H 0.260896|
|14||C -0.121432||H 0.248682||H 0.280168|
|15||C -0.454235||H 0.254663||H 0.257812|
|16||C -0.605286||H 0.242716||H 0.225737|
|17||C 0.360928||H 0.236793||H 0.242777|
|18||O -0.380013||H 0.261176||H 0.242759|
From Table 8, Fig. 7, it clear that the high negative carbon atom at position 1 in the free radical of NAC will be attached to the higher positive charged carbon atom at position 2 in the benzene ring of the free radical of m-PA. The N-acetylcysteine will be attached at position 2 in the ring since the hydrogen atom attached this carbon atom at position 14 has less positive charge, therefore, there is a competitive attraction between H 14 in the ring of m-PA and the highly negative C1 in NAC. Hence C1 in NAC will be attached with the ring of m-PA at position 2. The positive hydrogen atom at position 14 will be attracted with the negative nitrogen atom at position 7 producing amino-hydrogen at this position, and the quinoide structure of m-PA will disappear producing another molecule preventing the formation of the quinoide structure as in m-PA which is responsible for the cancer effect. The hydrogen atom at position 10 in NAC free radical has a high positive charge which will be attracted to high negative charge, therefore, proton transfer from C1 to N3 to permit the attachment between C1 in NAC to C2 in the m-PA free radical
FIG. 7: THE MINIMUM ENERGY STRUCTURES OF THE FREE RADICALS OF NAC AND m-PA
FIG. 8: THE INTERACTION BETWEEN m-PA AND NAC
June 2009, an FDA advisory committee recommended that new restrictions should be placed on Paracetamol usage in the United States to help protect people from the potential toxic effects. The maximum dosage to be consumed at any given time would be decreased from 1000 mg to 650 mg, while combinations of Paracetamol and narcotic analgesics would be prohibited. Committee members were particularly concerned by the fact that the present maximum dosages of Paracetamol had been shown to produce alterations in hepatic function. The FDA has not implemented its recommendations as of October 2010.
TABLE 8: THE CHARGE DENSITIES OF THE FREE RADICALS OF NAC AND m-PA
|1||C 0.044547||C -1.003289||C 0.012310|
|2||O -0.145295||S 0.397550||C -0.600503|
|3||C -1.320108||N -0.206871||O -0.343951|
|4||C -0.227236||C 0.540236||N -0.361189|
|5||C -0.224849||O -0.465326||C -0.069797|
|6||C -0.079104||C -0.746486||C 0.378164|
|7||O -0.403142||C 0.338204||O -0.470179|
|8||O -0.576282||C -0.820600||C -0.628453|
|9||O -0.346952||O -0.388053||C -0.786407|
|10||O -0.484174||H 0.335015||S 0.447818|
|11||N -0.061105||H 0.068367||C -0.923976|
|12||C 0.614239||H 0.462384||H 0.184305|
|13||O -0.459002||H 0.244840||H 0.233699|
|14||C -0.781099||H 0.248682||H 0.464186|
|15||H 0.226279||H 0.254663||H 0.215990|
|16||H 0.268590||H 0.242716||H 0.234493|
|17||H 0.232670||H 0.236793||H 0.240787|
|18||H 0.260592||H 0.261176||H 0.249389|
|19||H 0.256456||H 0.238037|
|20||H 0.461922||H 0.266902|
|21||H 0.484443||H 0.286863|
|22||H 0.501197||H 0.240635|
|23||H 0.474750||H 0.243739|
|24||H 0.528768||H 0.247138|
FIG. 9: THE THREE PATHWAYS OF PARACETAMOL IN THE LIVER
TABLE 9: DFT/6-31G**.CHARGE DENSITIES OF THE N-ACETYLMETHIONINE AND N-ACETYLGLUCOSAMINE WITH RESPECT TO N-ACETYLCYSTEINE
|NAC free radical||m-PA free radical|
|1||C -1.006906||C 0.349037|
|2||S 0.430132||C 0.384714|
|3||N 0.239680||C -0.906151|
|4||C 0.100551||C -0.002261|
|5||O -0.363729||C -0.271942|
|6||C -0.598040||C -0.298343|
|7||C 0.340232||N -0.160492|
|8||C -0.670558||C 0.689206|
|9||O -0.372600||C -0.914644|
|10||H 0.375061||O -0.448519|
|11||H 0.071781||O -0.581359|
|12||H 0.220141||H 0.293696|
|13||H 0.253135||H 0.211427|
|14||H 0.242265||H 0.259567|
|15||H 0.237844||H 0.244277|
|16||H 0.211060||H 0.217471|
|17||H 0.289948||H 0.238823|
N-Acetylmethionine has charge density 0.464186, Table 9, at amino-hydrogen atom at position 14, Fig. 10, which isn’t far from the charge density value of amino-hydrogen atom at position 12 in NAC molecule, Fig. 10, therefore, they behave similarly toward N-Acetyliminoqunone (m-PA).
N-Acetylglucosamine (NAGA) has higher charge density, 0.528768, Table 9, in the amino-hydrogen atom at position 24, Fig. 10, therefore it is expected that NAGA is more efficient to remove the carcinogenic effect of Paracetamol than NAC and NAM from the charge density point of view.
From Table 10, it is obvious that the studied molecules (NAC, NAM, and NAGA) and their free radicals, Fig. 11, have small comparative Ea and Ip values with respect to those of nucleic acid bases, therefore, there is not apprehension to make an electron transfer with them, Table 1. From Table 10, it clear that the energy barrier E between NAM molecule and its free radical (F.R.), Fig. 11, has the lowest value, 18.89 eV.
This means the alteration of the NAM molecule is easier to be free radicals which combine with N-Acetyliminoquinone (m-PA) to remove its quinoide structure. Hence the removal of m-PA means the removal of the carcinogenic effect of Paracetamol drug.
TABLE 10: DFT PARAMETERS OF NAC, NAM AND NAGA
|Molecule||E au||Ip au||eV||Ea au||eV||ΔE eV||Dip. D|
CONCLUSION: Paracetamol and Phenacetin as drugs are safe from the cancer effect in the presence of N-acetylcysteine, N-acetylmethionine, or N-Acetylglugosamine.
ACKNOWLEDGEMENT: This work has been supported by the Egyptian Ministry of Higher Education, Management of Supporting Excellence, Competitive Excellence Project of Higher Education Institutions, (project: CEP1-043-ASSU), Grant 2014.
CONFLICT OF INTEREST: Nil
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How to cite this article:
El-Shahawy A, El-Maali NA and El-Hawary HH: Averting cancer effect of paracetamol and phenacetin by n-acetylcysteine and its analogues. Int J Pharm Sci & Res 2014; 5(10): 4159-69. doi: 10.13040/IJPSR.0975-8232.5(10).4159-69.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
A. El-Shahawy. N. A. El-Maali and H. H. El-Hawary
Department of Chemistry, Faculty of Science, Assiut University, Egypt.
23 March 2014
19 June 2014
09 July 2014
01 October 2014