Aspirin (Analgesic) and Dicamba (Herbicide): Electron Transfer

Downloaded by KTH ROYAL INST OF TECHNOLOGY on January 12, 2016 | http://pubs.acs.org Publication Date (Web): October 13, 2015 | doi: 10.1021/bk-2015-1200.ch011

Chapter 11

Aspirin (Analgesic) and Dicamba (Herbicide): Electron Transfer, Reactive Oxygen Species, Oxidative Stress, and Antioxidant Peter Kovacic1,* and Ratnasamy Somanathan1,2 1Department

of Chemistry and Biochemistry, San Diego State University, San Diego, California 92182-1030, United States 2Centro de Graduados e Investigación del Instituto Tecnológico de Tijuana, Apdo postal 1166, Tijuana, B.C. Mexico *E-mail: [email protected]

Although aspirin is an analgesic and dicamba is an herbicide, both are derivatives of salicylic acid and both undergo similar metabolic transformation. The salicylic acid type of metabolite can be regarded as the key to physiological action. Subsequent hydroxylation to catechol or hydroquinone derivatives would lead to o- or p- quinones. The quinones generate ROS which can be involved in therapy or toxic reactions. AO properties are attributed to phenolic metabolites. The existence of favorable and harmful effects of phenol is rationalized. The unifying mode of action can be applied generally to analgesics and herbicides. The CNS plays an important role. The phenol group of various analgesic drugs or their metabolites (acetaminophen, aleve, morphine and aspirin) represents a common feature of mechanistic significance. Keywords: Aspirin; CNS; dicamba; oxidative stress; radicals

electron transfer;

Introduction This review deals with acetyl salicylic acid (aspirin) (ASA) (Fig 1), an analgesic, and dicamba (Fig. 2), an herbicide, in relation to similarities and

© 2015 American Chemical Society In Oxidative Stress: Diagnostics, Prevention, and Therapy Volume 2; Hepel, Maria, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


physiological activity. A prior unifying, mechanistic theme is applied as follows (1).

Figure 1. Aspirin

Figure 2. Dicamba “The preponderance of bioactive substances, usually as the metabolites, incorporate ET functionalities. We believe these play an important role in physiological responses. The main groups include quinones (or phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced hydroxylamine and nitroso derivatives), and conjugated imines (or iminium species). Resultant redox cycling is illustrated in Scheme 1. In vivo redox cycling with oxygen can occur, giving rise to oxidative stress (OS) through generation of reactive oxygen species (ROS), such as hydrogen peroxide, hydroperoxides, alkyl peroxides, and diverse radicals (hydroxyl, alkoxyl, hydroperoxyl, and superoxide) (Scheme 2).

Scheme 1. Redox cycling with superoxide formation

Scheme 2. Other ROS from superoxide 270 In Oxidative Stress: Diagnostics, Prevention, and Therapy Volume 2; Hepel, Maria, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


In some cases ET results in involvement with normal electrical effects (e.g., in respiration of neurochemistry). Generally, active entities possessing ET groups display reduction potentials in the physiologically responsive range, (i.e., more positive than about -0.5 V). Hence, ET in vivo can occur resulting in production of ROS which can be beneficial in cell signaling at low concentrations, but produce toxic results at high levels. Electron donors consist of phenols, N-heterocycles or disulfides in proteins which produce relatively stable radical cations. ET, ROS and OS have been increasingly implicated in the mode of action of drugs and toxins, (e.g., antiinfective agents (2), anticancer drugs (3), carcinogens (4), reproductive toxins (5), nephrotoxins (6), hepatotoxins (7), cardiovascular toxins (8), nerve toxins (9), mitochondrial toxins (10), abused drugs (11), pulmonary toxins (12), ototoxins (13), and various other categories (14). There is a plethora of experimental evidence supporting the ET-ROS theoretical framework. This evidence includes generation of the common ROS, lipid peroxidation, degradation products of oxidation, depletion of AOs, effect of exogenous AOs, and DNA oxidation and cleavage products, as well as electrochemical data. This comprehensive, unifying mechanism is consistent with the frequent observations that many ET substances display a variety of activities (e.g., multiple-drug properties), as well as toxic effects. It is important to recognize that mode of action in the biodomain is often multifaceted. In addition to the ET-ROS-OS approach, other aspects may pertain, such as, enzyme inhibition, allosteric effects, receptor binding, metabolism and physical factors. A specific example involves protein binding by quinones in which protein nucleophiles, such as amino or thiol, effect conjugate addition.” It is interesting that ASA and dicamba possess related structures and undergo similar metabolism. The unifying modes of action are applicable to both agents in relation to activity and toxicity. The approach is a continuation of prior reports dealing with the unifying mechanism, including the central nervous system (CNS).

ET-ROS-OS-AO Mechanism for Aspirin Various reports exist that support the unifying mode of action, as applied to ASA (2). “Some of the metabolic pathways have been quite well delineated, such as the first step entailing deacetylation of acetyl salicylic acid by esterase to yield salicylic acid (Fig. 3). Under appropriate conditions, oxidative metabolism gives rise to 2,5-dihydroxy-and 2,3-dihydroxybenzoic acids (Fig. 4 and 5). Quite plausibly, subsequent facile conversion to the o- and p- quinones (Fig. 6 and 7) can set the stage for redox cycling by ET with induction of OS. Alternatively, salicylic acid avidly chelates iron to furnish a complex with potential ET properties. The scenarios are buttressed by evidence for ROS and lipid peroxidation.” Redox cycling by quinones is illustrated in Scheme 3.

271 In Oxidative Stress: Diagnostics, Prevention, and Therapy Volume 2; Hepel, Maria, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 3. Salicylic acid

Figure 4. Hydroquinone metabolite of SA

Figure 5. Catechol metabolite of SA

Figure 6. o-Benzoquinone-3-carboxyl

Figure 7. p-Benzoquinone-2-carboxyl 272 In Oxidative Stress: Diagnostics, Prevention, and Therapy Volume 2; Hepel, Maria, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Scheme 3. Redox cycling by p-benzoquinone A 2005 report deals with reaction of hydroxyl radicals with SA at the lead dioxide electrode (15). The radical is commonly generated in vivo from hydrogen peroxide, serving as an oxidant and hydroxylating agent. In the electrode reaction, the amount of 2,5-dihydroxybenzoic acid is much more than that of 2,3-isomer. Radical substitution reactions are apparently involved. SA induced OS in the form of hydrogen peroxide in root cultures (16). In more recent studies, ASA induces OS with associated complications, including mitochondrial dysfunction (17). We theorize that the dysfunction may involve ET interference with ET in the mitochondrial chain. Altered GSH redox metabolism plays a crucial role in ASA induced toxicity. Treatment of the cells with the thiol AO N-acetylcysteine attenuated the adverse effects which, we suggest might involve ROS. SA is not only a metabolite of ASA, but it is also an anti-inflammatory drug (18). The metabolite induces formation of thiobarbituric acid reactive substances (TBARS) which is indicative of ROS. Antioxidants suppressed TBARS generation, suggesting involvemnent of ROS. Results indicate that SA induces lipid peroxidation which is related to oxidative metabolism. Findings point to triggering of mitochondrial dysfunction by SA leading to lethal liver cell injury by lipid peroxidation. AO effects of ASA and SA were examined in rats (19). SA reduced OS, and large amounts of ASA are needed to produce an AO effect, apparently via liver generation of AOs. The effects of SA as AO were more intense than for ASA (20). ASA reduced OS, but only at high concentration. The AO effect may reflect metabolism to SA which could be the actual AO since phenols are well known AO agents, e.g., vitamin E. SA plays an important role in the cytoprotective effect in brain tissue. A review shows action as AOs and pro-oxidants, depending on condition (21).

Commonality Involving COX and ET-ROS-OS Mechansim There is evidence that drugs that metabolize to phenols can operate by inhibition of COX enzymes which can function as peroxidases (21, 22). In the process, the drug undergoes oxidation in which it functions as an AO, a common property of phenols (23), e.g., vitamin E. The phenols can also act as pro-oxidants, which applies to aspirin via metabolism to an ET quinone resulting in generation 273 In Oxidative Stress: Diagnostics, Prevention, and Therapy Volume 2; Hepel, Maria, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


of ROS and OS. Oxidation of the drug or metabolites leads to reduction or inhibition of the COX enzymes (21, 22). Previously, the two mechanisms were regarded as separate and diverse pathways. This novel perspective reveals that the two are intimately associated with the COX enzyme acting as a peroxidase oxidant of the drug with conversion to the ET quinone metabolite. This represents an expansion of the unifying feature. There has been extensive literature on COX enzymes. COX appears to play a role in aspirin action.

ASA, CNS and COX In addition to treatment of this aspect in other sections, some recent literature is presented. ASA impairs ganglion neurons by inducing an increase in superoxide resulting in apoptosis (24). After ASA administration, GABA and serotonin mediated neurotransmission in the CNS resulted in hyperactivity. A large amount of the drug produced increased current flow into the auditory cortex. Inhibition of COS produces many of the adverse reactions of NSAIDs, including aspirin, which reduce prostaglandin synthesis in the CNS (25).

Aspirin Toxicity This topic has been reviewed recently (26). Salicylate ingestion in excess is a common cause of poisoning in children, which has improved in recent years. The adverse effects are characterized by many symptoms, including hyperventilation, dehydration, hypokalemia, acidosis, nausea, vomiting, diaphoris, tinnitus, vertigo, tachycardia, hyperactivity, agitation, delirium, hallucination, convulsions, lethargy, and stupor. Hyperthermia indicates severe toxicity, especially in children. When used properly, aspirin is not a dangerous drug, and is consumed in vast quantities.

Dicamba Metabolism A key aspect involves demethylation of the ether resulting in the phenolic groups of the 2,5-dichloro SA derivative (Fig. 8) (27, 28). Mechanistically, there are two possible routes for the transformation. One comprises hydrolysis which is depicted in Scheme 4. The other consists of radical oxidation that entails a hemiacetal metabolite in Scheme 5. Subsequent oxidation would lead to the hydroquinone (Fig. 9) and p-benzoquinone (Fig. 10) derivatives.

Figure 8. 2,5-Dichlorosalicylic acid 274 In Oxidative Stress: Diagnostics, Prevention, and Therapy Volume 2; Hepel, Maria, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Scheme 4. Acid catalyzed hydrolytic demethylation of ArOCH3

Scheme 5. Oxidative radical demethylation of ArOCH3

Figure 9. Hydroquinone derivative of Dicamba

Figure 10. p-Benzoquinone-2-carboxyl-3,6-dichloro

Dicamba Toxicity Data reveal that the herbicide is moderately to slightly toxic (29), In female, pregnant rabbits there was slightly reduced fetal weight and increased loss of fetuses. With dogs, some enlargement of liver cells occurred, but not in humans. Dicamba was found to be slightly toxic to cold water fish. 275 In Oxidative Stress: Diagnostics, Prevention, and Therapy Volume 2; Hepel, Maria, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Unifying Mechanism of Herbicide Toxicity The mode of toxicity described for dicamba fits into a broader scenario that has been proposed for other members of this general class involving the CNS (30). The bipyridyl herbicides, paraquat (Fig. 11) and diquat (Fig. 12), belong to this class for which the mode of action has been well established, in line with ET-ROS-OS. Extensive evidence supports redox cycling with formation of superoxide and other ROS, as illustrated in Scheme 1 and 2. It is well documented that ROS play a significant role in toxicity. The agents are conjugated iminiums which belong to the ET class (see Introduction).

Figure 11. Paraquat

Figure 12. Diquat

The diphenylether herbicide, e.g., oxylluorfen (Fig. 13) and fluorodifen (Fig. 14), also fit the unifying theme since they are ET agents of the ArNO2 type (see Introduction). In the case of oxyfluorfen, the structure also contains an ethyl ether group capable of dealkylation to a phenol, with potential for subsequent ET quinone formation via diol (see Introduction). This class appears to act by generating various ROS, resulting in lipid peroxidation and other oxidative damage. Another factor may involve ET during enzyme inhibition in the mitochondrial ET chain.

Figure 13. Oxyfluorfen 276 In Oxidative Stress: Diagnostics, Prevention, and Therapy Volume 2; Hepel, Maria, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 14. Fluorodifen About 50% of the herbicide groups operate by inhibition of ET chains, in accord with the unifying theory, including diuron and atrazine. The process involves increased lipid peroxidation which may be caused by singlet oxygen.

Commonality of Aspirin and Dicamba There are pronounced structural similarities. Both are benzoic acid and phenolic derivatives. In metabolism, salicylic acid or the dichloro derivative are the principal metabolites produced. The two agents are alike in displaying slight to moderate toxicity in humans and other animals. The differences can be attributed to effect of chlorine, different receptors, and different sites of action.

Other Analgesics and Related Drugs Drugs that belong in this class include benzodiazepines (tranquilizers), phenobarbital (sedative painkiller), phenytoin (anti-epilepsy), and morphine and heroin (analgesics) which are treated in more details in the acetaminophen chapter.

Abbreviations ET= electron transfer; ROS= Reactive oxygen species; OS= oxidative stress; AO= antioxidant; ASA= acetyl salicylic acid (aspirin); SA= salicylic acid; CNS= central nervous system

Acknowledgments Editorial assistance by Thelma Chavez is acknowledged.

References 1. 2. 3. 4. 5. 6.

Kovacic, P.; Somanathan, R. Curr. Bioact. Compd. 2010, 6, 46–59. Kovacic, P.; Becvar, L. E. Curr. Pharm. Des 2000, 6, 143–167. Kovacic, P.; Osuna, J. A. Curr. Pharm. Des. 2000, 6, 277–309. Kovacic, P.; Jacintho, J. D. Curr. Med. Chem. 2001, 8, 773–796. Kovacic, P.; Jacintho, J. D. Curr. Med. Chem. 2001, 8, 863–892. Kovacic, P.; Sacman, A.; Wu-Weis, M. Curr. Med. Chem. 2002, 9, 823–847. 277 In Oxidative Stress: Diagnostics, Prevention, and Therapy Volume 2; Hepel, Maria, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.

7. 8. 9. 10.


11. 12.

13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.

24. 25. 26. 27. 28. 29. 30.

Poli, G.; Cheeseman, K. H.; Dianzani, M. U.; Slater, T.F. Free Radicals in the Pathogenesis of Liver Injury; Pergamon: New York, 1989; pp 1−330. Kovacic, P.; Thurn, L. A. Curr. Vasc. Pharmacol. 2005, 3, 107–117. Kovacic, P.; Somanathan, R. Curr. Med. Chem. 2005, 5, 2601–2623. Kovacic, P.; Pozos, R. S.; Somanathan, R.; Shangari, R.; O’Brien, P. J. Curr. Med. Chem. 2005, 5, 2601–2623. Kovacic, P.; Cooksy, A. L. Med. Hypotheses 2005, 64, 357–367. Kovacic, P.; Somanathan, R. In Reviews of Environmental Contamination and Toxicology; Whitacre, D. E., Ed.; Springer: New York, 2009; Vol. 201, pp 41−69. Kovacic, P.; Somanathan, R. Med. Hypotheses 2008, 70, 914–923. Halliwell, B.; Gutteridge, J. M. C. Free Radicals in Biology and Medicine; Oxford University Press: New York, 1999; pp1−897. Ai, S.; Wang, Q; Li, H.; Jin, L. J. Electroanal. Chem. 2005, 578, 223–229; DOI:10.1016/j.jelechem.2005.01.002. Ali, M. B.; Hahn, E.-J.; Paek, K.-Y. Molecules 2007, 12, 607–621. Raza, H.; John, A. PLOS ONE 2012; DOI: 10.137/journal.pone.0036325. Hirokazu, D.; Toshiharu, H. Chem.-Biol. Interact. 2010, 183, 363–368. Guerrero, A.; González-Correa, J. A.; Muńoz-Marìn, J.; Sánchez-De La Cuesta, F.; De La Cruz, J. P. Neurosci. Lett. 2004, 358, 153–156. De La Cruz, J. P.; Guerrero, A.; González-Correa, J. A.; Arrebola, M. M.; Sánchez-De La Cuesta, F. J. Neurosci. Res. 2004, 75, 280–290. Kovacic, P.; Somanathan, R. In Frontires in Antioxidants Research; Panglossi, H. V., Ed.; Nova: New York, 2006; Chapter 1, pp 1−38. Davies, M. J.; Day, R. O.; Mohamudally, A.; Scott, K. F. Inflammopharmacology 2013, 21, 201–232. Vane, J. R., Botting, J. H., Eds. In Selective COX-2 inhibitors: Pharmacology, Clinical Effects and Therapeutic Potential; Kluwar Academic: 1998, pp 1−150. Sheppard, A.; Hayes, S. H.; Chen, G. D.; Ralli, M.; Salvi, R. Acta Otorhinolaryngol. Ital. 2014, 34, 79–93. Bovill, J. G. Eur. J. Anesthesiol. 1997, 15, 9–15. Waseem, M. Medscape: Drugs, Diseases and Procedures; Corden, T. E., Ed.; March 15, 2013. Gu, J.-G.; Han, B.; Duan, S. Int. Biodeterior. Biodegrad. 2008, 62, 455–459. Lin, C.; Gu, J.-G.; Qiao, C.; Duan, S.; Gu, J.-D. Biol. Fertility Soil 2006, 42, 395–401. Wikipedia, Aug. 2014. Halliwell, B.; Gutteridge, J. M. C. Free Radicals in Biology and Medicine; Oxford University Press: New York, 2000; pp 510−514.

278 In Oxidative Stress: Diagnostics, Prevention, and Therapy Volume 2; Hepel, Maria, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.

Aspirin (Analgesic) and Dicamba (Herbicide): Electron Transfer

Recommend Documents