Imatinib: Major photocatalytic degradation pathways in aqueous media and the relative toxicity of its transformation products
Graphical abstract
Introduction
Nowadays, pharmaceutical substances and/or their metabolites are emerging pollutants due to the inappropriate disposal of unused drugs, their excretion by humans or animals, as well as their low biodegradability or non-biodegradability in wastewater treatment plants. Due to their intrinsic activities, the presence of these pollutants, even at very low concentrations, may be associated with a risk to human health and other species (Luo et al., 2014). It is therefore an important issue for environmental research, particularly for pharmaceutical pollutants having cytotoxic, cytostatic and endocrine therapy activities (Heath et al., 2016) due to mutagenic and estrogenic effects, which can already occur at very low levels in μg·L−1 and ng·L−1, respectively (Parrella et al., 2014a).
Once in water, pharmaceuticals can undergo biotic and abiotic transformations leading to transformation products (TPs), possibly more persistent and more toxic than the parent compound and it is now well established that these may have environmental impacts (DellaGreca et al., 2014; Kümmerer, 2009; La Farré et al., 2008). In the precise case of cytotoxic, cytostatic and endocrine therapy drugs, it was showed that some TPs can exert higher mutagenicity and/or estrogenic activity than the parent compound itself (Knoop et al., 2018; Toolaram et al., 2014; Larcher et al., 2012).
Imatinib (IMA), a first-line anti-cancer agent used in the treatment of chronic myeloid leukemia (Hehlmann et al., 2017; Sacha, 2013; Druker et al., 2001) can produce such effects at concentrations below 1 ng·mL−1 (Mendoza et al., 2015; Besse et al., 2012). A study using the comet test on C. dubia showed that an IMA concentration of 300 pg·mL−1 could induce DNA damage (Parrella et al., 2015). Besides, due to its endocrine disrupting activities, IMA has been shown to cause growth retardation in children treated for leukemia (Bansal et al., 2012) and induce effects on MCF-7 cell at concentrations below 0.1 pg·mL−1 (Parrella et al., 2014b). This is worrying since its environmental concentration in France, England and Portugal has been estimated at a level around 5 ng·L−1 (Santos et al., 2017; Booker et al., 2014; Besse et al., 2012).
Despite IMA is a drug that may induce effects on the environment, only a few studies have been implemented to assess the fate of IMA and the impact of its TPs in water. Studies aimed at revealing IMA degradation under hydrolytic, oxidative and photolytic stress in pharmaceutical context (Nageswari et al., 2012). It was found that IMA is practically stable under neutral, weak acidic and basic conditions, and may only be degraded when strong acidic and alkali conditions, irrelevant to environmental conditions are applied. Though IMA absorbs light in the visible range (Szczepek et al., 2007), it was not degraded at pH 7.4 under simulated light and no triplet-excited state was detected by fluorescence or laser flash photolysis measurements. This may be explained by the presence of a substructure in IMA that acts as a self-quencher at this pH (Nardi et al., 2014). However, Fiszka Borzyszkowska et al. (2016) showed that at higher pH, the compound became more sensitive to light.
In view of these elements, it is very likely that IMA-related compounds would be formed mainly by oxidation and/or in the presence of radicals, either during IMA's exposure to an advanced oxidation process (AOP) or once it is present in the environment. Generally, AOPs are based on the in situ formation of a powerful oxidizing agent, such as hydroxyl radicals (OH) (Oturan and Aaron, 2014).
In natural surface waters, a wide variety of molecules are degraded through the formation of reactive oxygen species (ROS) which are capable of oxidizing them with relatively low selectivity (Westerhoff et al., 2007; Canonica et al., 2005; Brezonik and Fulkerson-Brekken, 1998). Among all ROS, the impact of OH, being ubiquitous and one of the most powerful oxidizing agents is surely to be studied in detail (Gligorovski et al., 2015). Indeed, in the presence of hydroxyl radical (OH), drugs may undergo oxidation reactions forming TPs whose persistence and toxicity may potentially differ from those of the parent molecule (Knoop et al., 2018; DellaGreca et al., 2014; Kümmerer, 2009; La Farré et al., 2008). Thus, understanding the chemical reactivity of IMA towards OH is therefore an important first step to understand the IMA environmental significance. Currently, no information on the nature and toxicity of IMA TPs upon OH stress is available.
In this respect, a TiO2-based photoactive material was used for the generation of one of the most commonly involved ROS in drug transformation, i.e.OH, in order to create the conditions that could lead to the formation of some of IMA TPs when AOPs are used or when it is discharged unchanged in the environment (Calza et al., 2016; Sakkas et al., 2011). Without having characterized the IMA TPs resulting from photocatalysis, Borzyszkowska et al. nevertheless showed that IMA degrades in the presence of TiO2 and that the use of a doped material accelerates the process (Fiszka Borzyszkowska et al., 2016).
LC-HRMSn was used to identify IMA TPs (Singer et al., 2016). Theoretical simulations using a method of Density Functional Theory (DFT) were performed to provide additional information to get insight into the transformation process. In silico and in vitro studies having proven to be a useful approach for the assessment of organic compounds ecotoxicity (Escher and Fenner, 2011; Menz et al., 2017; Sinclair and Boxall, 2003), both of these approaches were employed to study the toxicity of the TPs. In silico QSAR toxicity studies with respect to mutagenicity and estrogen activity were carried out for each TP. In vitro toxicity studies were conducted to study the acute toxicity of the mixtures of IMA with its TPs obtained in the photocatalytic experiments by following V. fischeri bioluminescence inhibition using the Microtox assay under basic test conditions.
Section snippets
Materials and reagents
IMA (imatinib mesylate, purity >99%) and TiO2 (99.5% Aeroxide® P25, nanopowder, average primary particle size 21 nm) came from Sigma Aldrich (St. Quentin Fallavier, France). The structural properties of P25 TiO2 are: 21 nm primary particle size, surface area 35–65 m2·g−1 and purity ≥99.5% (Sigma Aldrich).
The ultrapure water was produced by the Q-Pod Milli-Q system (Millipore, Molsheim, France). Formic acid, isopropanol, methanol and acetonitrile (LC-MS grade) were purchased from VWR Prolabo®
IMA photocatalytic degradation: kinetics and TPs formation
The photocatalytic degradation kinetics of the IMA was studied and the corresponding results summarized in Fig. 1. The IMA was completely degraded after 240 min of irradiation based on a TiO2 concentration of 500 μg mL−1, with an initial concentration of 100 μg mL−1 and in the presence of a pH ranging from 5.7 to 6.0.
To determine the relative contribution of the surface reaction with h+, OH radicals and other ROSs, such as O2−, HO2 and H2O2 on the degradation kinetics, different scavengers were
Conclusion
In the present work, the reactivity of IMA in TiO2-containing waters was investigated for the first time. The non-targeted screening approach proposed in this study allowed the detection of 12 TPs (11 of them previously unreported), showing its potential in environmental analysis. These TPs were tentatively identified on the basis of their accurate-mass spectra (full-scan and HRMSn) obtained by HPLC-Orbitrap mass spectrometry. Three main photocatalytic transformation pathways of the IMA in the
Acknowledgements
The authors want to thank K. Manerlax and M. Bimbot for their very appreciable contributions to this work. They are also thankful to Ile de France Region for financial support in the acquisition of the Orbitrap Velos Pro mass spectrometer.
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2021, Science of the Total EnvironmentCitation Excerpt :Hence, less confidence would be provided with this prediction, except for the compound 5-fluorouracil. Nevertheless, QSAR predicted the toxicity of tamoxifen and imatinib's transformation products where only their chemical structures were obtainable (Negreira et al., 2015; Secrétan et al., 2019). From the results obtained, most of the anticancer drugs studied achieved a risk quotient below one, suggesting that they do not pose any risk for the aquatic environment.
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2021, Science of the Total EnvironmentCitation Excerpt :The fragment ion m/z 99.09192 corresponding to non-oxidized methylpiperazine is also evident, which implies weak oxygen bonding and thus TP510 was identified as imatinib piperazine-N-oxide, which has been previously reported as IMA metabolite (Gschwind et al., 2005). In summary, we identified 8 TPs of IMA, of which one, TP510 was reported before (Secrétan et al., 2019), while TP426 was reported as a human metabolite (Gschwind et al., 2005). TP235, TP221, TP278, TP263, TP320 and TP378 are herein identified for the first time.