(Mechanism of Bactericidal Action and Toxicity): Metabolism, Electron

Chapter 8

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Triclosan (Mechanism of Bactericidal Action and Toxicity): Metabolism, Electron Transfer and Reactive Oxygen Species 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]

Triclosan, a widely used bactericide, has been the object recently of increased attention by the media and scientists in relation to safety and usefulness. This chapter deals with a unifying mechanism for antibacterial action and toxicity based on electron transfer (ET), reactive oxygen species (ROS) and oxidative stress (OS). The phenolic compound can be oxidatively converted to diols (catachol and hydroquinone types) which are then oxidized to o-or p-quinones. The quinones are ET agents capable of generating ROS which can act as either beneficial or toxic agents. Toxicity is associated with higher levels of ROS leading to OS. Mechanistic relationship to many physiologically active phenols is also addressed. This unifying action mode can be applied to other physiologically active ET agents. Keywords: Triclosan; bactericide; toxicity; metabolism; electron transfer; reactive oxygen species; phenols

Introduction In recent years, there has been increasing focus on triclosan (TCS) (Fig. 1), a bactericide, by the media and researchers. The agent has enjoyed widespread use, with recent enhanced attention to toxicity. Of relevance is a 2000 review © 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.


that deals with a unifying mechanism for anti-infective agents including TCS (1). The fundamental aspect involves electron transfer (ET), reactive oxygen species (ROS) and oxidative stress (OS). Although widespread discussion of ROS exists in the literature, there is less recognition of the role played by ET agents. The main categories of ET agents are quinones (or phenolic precursors), aromatic nitro compounds, metals (or complexors) and imine (or iminium) species. The focus of the present review is the quinone class as applied to TCS. Generation of superoxide by ET is depicted in Scheme 1. In Scheme 2, superoxide is shown as precursor of other ROS.

Figure 1. Triclosan (TCS)

Scheme 1. Redox cycling with superoxide formation

Scheme 2. Superoxide precursor of other ROS There has been extensive literature supporting the ET-ROS-OS approach, including anti-infective agents (1), anticancer drugs (2), carcinogens (3) and many toxins (toxicants) (4–17). It is prudent to adopt a multifaceted approach to mechanism of physiological action, with operation of pathways in addition to ET-ROS-OS. In the present report, mode of antibacterial action for TCS is addressed with emphasis on ET-ROS-OS. It is noteworthy that the unifying mechanism was first proposed as an hypothesis with scant supporting evidence (1). Since then, studies provide evidence for hydroxylation to diols (Fig 2 and 3) followed by formation of possible quinones (Fig 4 and 5). Numerous examples are provided of other phenols possessing various physiological activation in accord with the ET-ROS-OS approach. The mechanism can be applied to both therapy and toxicity. The beneficial route for anti-infective agent has been termed phagomimetic (18). Toxicity is limited to high and persistent levels of ROS and is commonly an undesirable effect that accompanies therapy. 238 In Oxidative Stress: Diagnostics, Prevention, and Therapy Volume 2; Hepel, Maria, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 2. Catechol derivative of TCS

Figure 3. Hydroquinone derivative of TCS

Figure 4. o-Quinone derivative of TCS

Figure 5. 5 p-Quinone derivative of TCS

Modes of Action Triclosan, a widely used antibacterial agent, has been the object of attention in research and the media. There is controversy concerning safety of the product. Considerable research has been devoted to the mode of action in relation to therapy and toxicity (19). Mechanisms proposed include muscle contraction, and inhibition involving enzymes , such as a protein reductase. Disruption of the endocrine system occurs via signaling, entailing action of androgens, estrogens and thyroid hormones. However, there has been little discussion of ET-ROS-OS which was addressed in 2000. The agent is a member of the phenolic class, many of which are 239 In Oxidative Stress: Diagnostics, Prevention, and Therapy Volume 2; Hepel, Maria, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


therapeutic agents, e.g., hexylresorcinol (Fig. 6) a related bactericide. According to the therapeutic approach, conversion to the active agents entails oxidation to diols (catechols and hydroquinones), followed by oxidative conversion to o- and p- quinones (Fig. 3 and 4) which are well known ET agents capable of generating ROS.

Figure 6. Hexylresorcinol The proposed metabolism for TCS in 2000 (1) has been supported by subsequent reports dealing with hydroxylation and quinone formation. In one case, hydroxylation occurred by treatment with the Fenton reagent yielding a p-hydroquinone (20). The system resembles in vivo metabolism since the hydroxyl radical serves as oxidant. The reaction was found to be highly efficient. When exposed to a bacterial strain, the drug underwent both monoand di-hydroxylation (21). The authors describe the drug as a “persistent environmental pollutant.” A report deals with oxidation by manganese oxides found in the soil which operate as facile oxidants (22). One of the main products is the p-hydroquinone, formed via involvement of phenoxy radicals. The most significant investigation was performed with TiO2 and hydrogen peroxide under irradiation by UV light (23). Oxidation took place at the phenol ring with generation of hydroquinone and quinone products. Possible quinones are indicated in Fig. 4 and 5, arising from 1,2-or 1,4-diols. A possible 1,3-dihydroxy (resorcinol) metabolite could also serve as a quinone precursor, as noted in a prior review (24). An alternative metabolic pathway entails degradation via cleavage of the diphenyl ether backbone (2, 20–22). A product is 2,4-dichlorophenol which might also display physiological activity by conversion to ET quinone with subsequent ROS generation. Bactericidal properties of the degraded phenol are reported (2). There is evidence from other phenols that supports the unifying mechanistic approach. Pentachlorophenol (PCP), 50 times more active than phenol, generates lipid peroxidation and enzyme deactivation by way of OS (1). Oxidative metabolites of PCP produce DNA cleavage via formation of ROS from redox cycling by tetrachlorosemiquinone radicals. Chlorine substituents facilitate the radical oxidation, as would be the case or triclosan. Closely related analogs in structure with various activities are hexylresorcinol (Fig. 6) (23), tetrahydrocannabinol (Fig. 7) (24), dopamine (Fig. 8) (10), 5-hydroxytryptamine (Fig. 9) (10), morphine (Fig. 10) (10), and salicylic acid (Fig. 11) (10) from aspirin. In many cases, benzenoid rings undergo oxidation to phenols with subsequent conversion to quinones, as for benzene (25) and phenolberbital (Fig. 12) (10). 240 In Oxidative Stress: Diagnostics, Prevention, and Therapy Volume 2; Hepel, Maria, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 7. Tetrahydrocannbinol

Figure 8. Dopamine

Figure 9. 5-Hydroxytriptamine

Figure 10. Morphine

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


Figure 11. Salicylic acid

Figure 12. Catechol derivative\of phenobarbital

Toxicity There is increasing concern about possible toxic effects of TCS. In relation to mode of action, the unifying mechanism can be applied involving attack by ROS leading to various adverse effects. Extensive prior literature exists that demonstrates a correlation between generation of ROS via quinone metabolites and harmful effects. Evidence involves lipid peroxidation, protein oxidation and cleavage, and attack of vital body organs. Other representative examples can be cited. Benzene, a well-known carcinogen, generates ROS-OS via metabolism to phenol, diols and quinones. Uroshiol (poison ivy) contains 3-pentadecyl catechol (Fig. 13) as an important component (26). Toxicity has been related to metabolic oxidation to an o-quinone. GSH, an antioxidant (AO) inhibits the adverce effects which evidently arise from harmful oxidation. Redox cycling by ET o-quinone apparently generates ROS which deplete AOs, resulting in further increase in ROS. 242 In Oxidative Stress: Diagnostics, Prevention, and Therapy Volume 2; Hepel, Maria, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 13. 3-Pentadecylcatechol

Abbreviations TCS= triclosan; ET= electron transfer agent; ROS= reactive oxygen species; OS= Oxidative stress; AO= antioxidant; PCP= pentachlorophenol

Acknowledgments Editorial assistance by Thelma Chavez is acknowledged.

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(Mechanism of Bactericidal Action and Toxicity): Metabolism, Electron

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