Environ. Sci. Technol. 2009, 43, 401–407
Transformation of Tetracyclines Mediated by Mn(II) and Cu(II) Ions in the Presence of Oxygen WAN-RU CHEN† AND CHING-HUA HUANG* School of Civil and Environmental Engineering, Georgia Institute of Technology Atlanta, Georgia 30332
Received August 17, 2008. Revised manuscript received October 31, 2008. Accepted November 4, 2008.
Complexation of tetracyclines (TCs) with dissolved MnII and CuII ions were found to significantly enhance the transformation of these antibiotics in the presence of oxygen at pH 8-9.5 and pH 4-6, respectively. In the TC-MnIIsO2 system, oxidation of the TC-complexed MnII to MnIII by oxygen occurs, followed by oxidation of TC by MnIII to regenerate MnII. In the TC-CuIIsO2 system, CuII oxidizes TC within the complex and the yielded CuI is reoxidized by the present oxygen. Opposite reactivity trends were observed with the two metals: OTC (oxytetracycline) > TTC (tetracycline) . iso-CTC (isochlorotetracycline) for the MnII-mediated reaction, whereas CTC > TTC > OTC > epimers for the CuII-mediated reaction. ThereactivityresultsandexaminationofTC-metalioncomplexation and transformation products suggest that the BCD-ring and A-ring of TC are crucial to interact with MnII and CuII, respectively. This study highlights that the fate of TCs in aquatic environments may differ significantly by their strong interactions with different metal species present in the systems.
Introduction Tetracycline antibiotics (TCs), such as tetracycline (TTC), oxytetracycline (OTC), and chlorotetracycline (CTC) (Figure 1) are used extensively to treat diseases for humans and in animal feed at subtherapeutic levels to prevent epidemics and increase the growth rate and weight gain in livestock and aquaculture (1). A large percentage of the administered TCs could be excreted from the treated hosts (2) and subsequently contaminate the environment via various routes including municipal wastewater effluent, biosolids, animal waste, and agricultural runoff. Recent studies have reported detection of TCs at around 0.15 µg/L in groundwater and surface waters (3), 86-199 µg/kg in soils, 4.0 mg/kg in liquid manure (4), and 3 µg/L in farm lagoons (5). The widespread use and frequent detection of TCs and other antibiotics in the environment have raised concerns over proliferation of antibiotic-resistant bacteria, decrease in the effectiveness of medical antibiotics, and other potential adverse human health and ecological effects (1, 6, 7). To accurately assess the risk of TCs, a thorough understanding of their fate in the environment is critical. TCs are complicated molecules with unique chemical behaviors that are summarized below. TC structures contain * Corresponding author phone: 404-894-7694; fax: 404-385-7087; e-mail:
[email protected]. † Current address: 520 Plant and Soil Science Building, Michigan State University, East Lansing, MI 48824. 10.1021/es802295r CCC: $40.75
Published on Web 12/11/2008
2009 American Chemical Society
connected ring systems (lettered A through D from right to left) with multiple ionizable functional groups (Figure 1). Three macroscopic pKa values were reported for the tricarbonylamide (C1-C3), phenolic-diketone (C10-C12) and dimethylamino groups (C4), respectively (8). The tricarbonylamide (A-ring) and phenolic-diketone (BCD-ring) are two separate resonance groups, contributing to two major absorption bands (250-300 nm and 340-380 nm) of TCs’ spectra (9-11). In addition to pH speciation, TCs may convert to other isomers depending on the TC compound and solution conditions. TCs can undergo reversible epimerization by changing the C4 dimethylamino group’s position to form the corresponding 4-epi-TCs (Figure 1). Epimerization gradually occurs at pH 2-6 (10), but may be enhanced by the presence of certain anions such as phosphate and citrate (12, 13). OTC has a lower tendency to epimerize than TTC and CTC possibly because its C5 hydroxyl group may form hydrogen-bonding with the dimethylamino group (14). At alkaline pH, TCs that have a C6 hydroxyl group cleave readily to from their respective iso-TCs (10) (Figure 1). CTC is especially prone to this irreversible transformation to yield iso-CTC quickly (15, 16). Because TCs possess multiple O- and N-functional groups, their strong tendency to complex with metals is well documented in the literature (9, 17). Depending on the chosen experimental conditions such as solvent medium; pH; metal ion type and ligand:metal ratio; complexation to the BCDring (18), A-ring (19), or both (9, 11, 20, 21) have all been suggested. The O10, O11, O12 on the BCD-ring and O1, O3, and N4 on the A-ring are among the coordination sites that were frequently proposed. Previous studies show that TCs may undergo abiotic degradation depending on pH, redox, and light conditions (22, 23), and are prone to adsorption to soils (24-26). The strong metal-binding tendency of TCs plays an important role in contributing to their strong interactions with mineral surfaces (24, 25, 27) and organic matter (28) and in affecting TCs’ photoreactivity in natural waters (29). For the similar reason, the in vivo antibiotic activity of TCs is dictated by their MgII and CaII complexes (30). Because TCs were shown to be readily oxidized by MnO2 (31, 32), it is possible that complexation with redox reactive metal ions may induce transformation of TCs. This work examined a range of metal ions including MnII, CuII, FeII, ZnII, MgII, and CaII for their potential effect on the transformation of TCs. Among them, MnII and CuII significantly enhanced oxidative transformation of TCs in the presence of oxygen. The focus of this work was to probe the mechanisms of the MnII- and CuII-promoted reactions by examining a range of TCs, their isomers, and reaction conditions.
Materials and Methods Chemicals. Sources of chemicals and reagent preparation are provided in Supporting Information (SI) Text S1. Reaction Setup. Batch experiments were conducted in 30 mL screw-cap amber glass bottles with Teflon septa at room temperature (22-25 °C). All reactions were homogeneous and thus no additional mixing was needed. Reactions with MnII were maintained at pH 8.0-9.5 with 10 mM 2-(cyclohexylamino)ethanesulfonic acid (CHES) buffer. This pH range was selected because the reaction of TCs with MnII is considerably slower at pH < 8 and the oxidation of MnII by dissolved oxygen becomes significant at pH > 9.0 (33). Reactions were initiated by adding antibiotic stock to solutions containing MnII ions, buffer, and constant ionic medium (0.01 M NaCl). Most experiments employed an initial VOL. 43, NO. 2, 2009 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
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FIGURE 1. Structures and properties of tetracyclines (TCs) and their isomers. antibiotic concentration of 40 µM to generate sufficient analytical signals for monitoring. Although potential selfassociation between TC molecules at high TC concentrations was suggested by previous studies (29), such interactions are not expected to be significant with the presence of an equal molar concentration or excess amount of metal ions in this study. Oxygen was purged to the reactors for 2 min every time after taking sample aliquots for analysis. Similar experiments but with nitrogen purging were conducted to evaluate the role of O2. Reaction aliquots were immediately quenched by adding HCl to pH ∼2 because little TC-metal complexation occurred at this low pH (18) and the metalfacilitated reaction was stopped. Note that TCs were stable in HCl solutions for long periods of time (10). Samples were stored in 2 mL amber vials at epi-TTC . iso-CTC (Figure 3a and SI Table S3). Opposite to the trend observed with MnII, the degradation rates with CuII (pH 5.0) were in the order of CTC > TTC . OTC ∼ epi-CTC > epi-OTC and epi-TTC (Figure 3b and Table S4). Complexation of TCs with MnII and CuII. The difference between MnII and CuII in promoting transformation of TCs may be related to how these two metal ions coordinate with TCs. Thus, complexation of TCs wth MnII and CuII was investigated. SI Figure S6a shows slight, but discernible, peak shifts of TTC’s UV spectrum at 290 and 350 nm when MnII was added at pH 9.0. Complexation with CuII at pH 5.0 caused severe peak broadening at 275 nm and a strong peak shift at 365-380 nm (SI Figure S6b). UV absorbance change (∆Abs) measured at increasing metal-to-TC ratio (Figures 4 and 5) indicates metal-TC complex formation due to metal ions perturbing TC’s chromophores, but does not distinguish specific complexes (i.e., 1:1, 1:2, and/or 2:1 metal-to-TC complexes); formation of 2:1 complex is possible at higher metal concentrations (11, 20, 21). To compare the complexation of various TCs with CuII in the same plot (Figure 5), the ∆Abs values for each TC compound at varying [CuII]/[TC] ratios were normalized by the ∆Abs value of its 1:1 complex. VOL. 43, NO. 2, 2009 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
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FIGURE 4. Absorbance changes at varying MnII-to-TC concentration ratio measured at (a) 290 nm and (b) 350 nm. Forty µM of TC (with 10 mM NaCl and 10 mM CHES buffer at pH 9.0) was titrated by 0-880 µM of MnCl2.
FIGURE 5. Absorbance changes at varying CuII-to-TC concentration ratio measured at specific wavelengths within (a) 276-286 nm and (b) 374-386 nm. Forty µM of TC (with 10 mM NaCl and 10 mM acetate buffer at pH 5.0) was titrated by 0-1000 µM of CuCl2. Figure 4 shows that, for TTC and OTC, ∆Abs decreased and then increased at 290 nm, whereas they decreased consistently at 350 nm with increasing [MnII] at lower metal concentrations before reaching a plateau at higher metal concentrations. Quite differently, iso-CTC exhibited ∆Abs increase at 290 nm with increasing [MnII], but little ∆Abs at 350 nm despite increasing [MnII]. According to the literature, TC’s A-ring chromophore contributes to the 250-300 nm absorption band only, whereas the BCD-ring chromophore contributes to both 250-300 nm and 340-380 nm absorption bands (9-11). Disruption of the phenolic-diketone resonance in iso-CTC resulted in its weak absorbance at 350 nm. While MnII complexation perturbed the 350 nm absorbance of TTC and OTC but not of iso-CTC, this result coincides with isoCTC’s inactivity to transformation by MnII/O2, raising the possibility that BCD-ring is the crucial site for the MnIImediated reaction. Figure 5 shows that both ∆Abs276-286 and ∆Abs374-386 increased with increasing [CuII] for all TCs, indicating CuII complexation perturbed both the A and BCD chromophores. However, only the perturbation at A chromophore (∆Abs276-286) agrees with the reactivity trend of TCs with CuII: CTC, with the highest ∆Abs276-286, had the fastest reaction rate, followed by TTC and then OTC. Furthermore, epi-TCs showed little A chromophore perturbation at [CuII]/[TC] > 1, coinciding with their very slow transformation by CuII. The above results suggest that A-ring is likely the crucial site for the CuII-mediated reaction. Transformation Product Evaluation. Reactions of TCs with MnII and CuII yielded different products. When analyzed by HPLC-UV, the transformation products from CuII-medi404
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ated reaction exhibited absorbance at 365 nm, whereas the products from MnII-mediated reaction did not (SI Figure S7). This result indicates that the MnII-mediated reaction destroyed the phenolic-diketone resonance in TCs, and supports the hypothesis that BCD-ring is the key reactive site with MnII. When analyzed by LC/MS, the MnII-mediated reaction of TTC yielded one (M + 14) and one (M + 16) products (M ) TTC molecular weight), suggesting insertion of oxygen. The CuII-mediated reaction yielded two (M - 18) and one dimer (m/z 849) products, suggesting water loss and radical coupling.
Discussion Proposed Reaction Mechanisms. Several factors must be considered to understand how MnII ions catalytically promote TC oxidation at pH 8.0-9.5 with the presence of oxygen. The oxidation rate of MnII by oxygen to yield MnIII and O2•- in simple aqueous media is proportional to [OH-] (2), and only becomes appreciable at pH > 9 (33). The half-life of MnII oxidation by oxygen is estimated at 60-611 h based on the conditions employed in this study (pH 9.0, P02 ) 0.21 atm, T ) 25 °C) and reported rate constants (33), considerably longer than the half-life of 44 h for TTC degradation by MnII/ O2. Furthermore, while the rate constant of TTC (OTC as well, data not shown) degradation increased from pH 8.05 to 9.43, the trend does not correlate well to the increasing rate constant of MnII oxidation by oxygen (33) (SI Figure S1). Lastly, the experiments with radical scavengers ruled out that O2•- or •OH was responsible for TTC loss. Thus, TC degradation in the TC-MnIIsO2 system was not due to
FIGURE 6. Proposed reaction schemes for the MnII-mediated, and (b) CuII-mediated transformation of TC.
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oxidation of free MnII by oxygen to generate MnIII, O2•-, and other ROS which then oxidize TC. Nowack and Stone (37, 38) reported a MnII-mediated oxidation of phosphonates in the presence of oxygen: the reaction began with complexation of MnII with phosphonate followed by oxidation of the phosphonate-complexed MnII to MnIII by oxygen and subsequent oxidation of phosphonate by MnIII to return to MnII. Overall, MnII participated in the redox reaction in a cyclic manner. For the TTC-MnIIsO2 system, the importance of MnII-TTC complexation for TTC degradation to occur was confirmed by (i) the inhibitory effect of competitor metal ions (MgII and CaII) and ligand (EDTA) on the reaction rate, and (ii) the increasing reaction rate with higher [MnII], which corresponds to a greater proportion of MnII-complexed TTC. The above observations resemble the study by Nowack and Stone, suggesting a similar mechanism is likely operative for TTC. As proposed in Figure 6a, the TC molecule first forms a strong complex with MnII, which facilitates the oxidation of MnII by O2. The generated MnIII then oxidizes TC within the complex to produce a TC radical and converts back to MnII. The TC radical may further react with oxygen or other radicals to yield the products. Overall, MnII plays a “catalytic” role in the oxidation of TCs by O2 and the cycle continues with sufficient oxygen. The O2•- formed may self-disproportionate to form other ROS (39), and may react with excess free MnII (40) or the oxidized TC intermediates. Similar to the MnII-mediated reaction, TC-CuII complexation is critical in the degradation of TC by CuII, evident by the inhibitory effect of competing ligand EDTA on the reaction (Figure 2b). However, the different needs for oxygen, reactivity trends among TCs, and product formation patterns with CuII versus with MnII clearly indicate different reaction mechanisms. As proposed in Figure 6b, the TC molecule first forms a strong complex with CuII. CuII is the oxidant within the complex to oxidize TC, forming CuI and a TC radical. Without oxygen, the TC radical can be further oxidized by CuII or couples with another TC radical to yield products, and CuI accumulates in the system as confirmed by its detection in oxygen-free experiments. When oxygen is present, it can intercept the TC radical to yield oxidation products, and oxidize CuI back to CuII. Overall, CuII participates in TC degradation in a regenerated cycle with oxygen as the ultimate oxidant. Although Quinlan and Gutteridge (41, 42) proposed that TTC, when complexed with CuII, caused oxidative damage to DNA bases due to generation of ROS, the results with radical scavengers and the distinctively different oxidation products by the MnII- versus CuII-mediated reactions in this study indicate that ROS did not drive the degradation of TCs in either reaction. The rate of TTC degradation increased with increasing pH in both MnII-mediated (pH 8.05-9.43) and CuIImediated (pH 4.0-5.5) reactions. At higher pH, TTC molecule is less protonated, which is favorable for both metal ion complexation and oxidation. Interestingly, SI Figure S1 shows that the rate of TTC degradation by MnII/ O2 correlated quite well to the mole fraction of the fully deprotonated (i.e., the most electron rich) species (L2-) as
pH was increased. The faster rate of MnII oxygenation at higher pH (33) may also contribute to the pH trend in SI Figure S1. The drop-off in k (SI Figure S2) in CuII-mediated transformation of TTC at pH 6.0 is not clear, and may be related to different pH buffer (MOPS) used than the other pH points (acetate). Reactive Moieties of TCs. The reactivity trend among TCs, spectroscopic complexation study, and product analyses together indicate that MnII and CuII mediate TCs’ transformation through interactions at different sites (i.e., BCD-ring and A-ring, respectively). This apparent site preference may be due to (i) the donor atoms at the particular moiety bind more favorably to the metal of interest (MnII vs CuII), and/or (ii) complexation to the particular moiety leads to specific electronic transition in the metal ion that favors its redox reaction. Previous studies suggest coordination of MnII to O-donor atoms of TC (21), whereas strong coordination of CuII with N-donor atoms is well-known (43). Thus, the respective reactive sites are consistent with ligand preference. Factor (ii) probably was more significant in the CuII-mediated reaction because excess CuII was utilized in the experiments and complexation to both BCD- and A-rings in a 2:1 metalto-TC complex likely formed despite that only complexation to the A-ring induced oxidation. The strong enolic π-to-π* transition in the A-ring (9) might be most suitable to facilitate CuII reduction. Among various TCs, if structural change by different substituents or conformation hinders complexation with the metal ion, lower reactivity is expected. This is supported by general observations that lower ∆Abs (i.e., weaker complexation) corresponded to lower reactivity when comparing different TCs in the MnII- or CuII-mediated reactions. While the current data is insufficient to delineate the mechanisms for the observed reactivity trends, the difference between the epimers versus their normal analogs can be discussed. Epimers showed particularly poor complexation with CuII at the A-ring and also very low reactivity to CuII-mediated reactions. TCs adopt different conformations depending on solution pH and metal complexation (9, 11, 12, 21). At basic pH, free TC adopts an extended conformation in which C1, C2, C3, and amide carbons lie above the BCD ring plan with H-bonding between N4 and OH12a. At acidic to neutral pH, owing to repulsion between the protonated dimethylammonium and OH12a groups, TC adopts a twisted conformation by twisting the A ring (9). Because of the different position of the dimethylamino group, epimers have different conformation than their normal analogs (12) and this difference apparently led to their poor complexation with CuII. The conformational factor may also be responsible for the stronger inhibitory effect of MgII than CaII on the MnIImediated reaction (SI Figure S4). Previous studies suggest that MnII-TTC (21) and CaII-TTC (11) complexes are in the extended conformation, whereas MgII-TTC complex adopts the twisted conformation (11). Precomplexation of TTC with CaII (at low metal concentration) may still permit complexation with MnII because of similar conformation, whereas precomplexation of TTC with MgII hinders complexation with MnII due to different conformational requirements. Environmental Significance. Manganese (II, III, and IV) and Cu(II) are common trace metals in natural waters and soils. Copper salts (e.g., copper sulfate) are also frequently used fungicides in agriculture (44). Both +II metal ions are capable of facilitating oxidative transformation of TCs by oxygen in a cyclic fashion, but via rather different mechanisms and at different TC structural moieties. This finding highlights that, with different metal species, the reactivity and transformation of various TC compounds VOL. 43, NO. 2, 2009 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
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may differ significantly depending on the involved metals. For example, accumulation of epimers is expected when CuII is the main metal species to facilitate oxidation of TCs. In natural waters, various metal ions and even mineral surfaces compete for complexation with TCs, although other ligands such as natural organic matter may also occupy some of the metal species. Based on the results that MgII and CaII inhibit the oxidation of TCs by MnII, and their much greater abundance in natural waters, the impact of MnII and CuII on the transformation of TCs will likely be diminished by such competing metal ions. Nevertheless, the concepts demonstrated in this study are still important and can be useful in exploring the reactions of TCs with other metal species and in developing selective degradation strategies for TCs.
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Acknowledgments This material is based upon work supported by the National Science Foundation under Grant 0229172.
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Supporting Information Available
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Text S1-S5, Tables S1-S4, and Figures S1-S7. This material is available free of charge via the Internet at http://pubs. acs.org.
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