Possible implementation of salicylate anions in lead detoxification

Lead is a neurotoxicant agent, which enters the body through digestion or inhalation and it is mainly accumulating in the human brain [1]. Primarily, it binds to erythrocytes, is distributed into the soft tissues (kidneys, liver, lungs, etc.) and ends up in bones and teeth, where it is stored [1]. Pb causes toxicity of the liver, kidneys, hematopoietic system, nervous system and cardiovascular system due to its exposure and accumulation [2]. Despite the efforts to minimize the Pb exposure, people are still at high risk due to the exposure in the workplace, through the air and the soil [3]. The most common symptoms of a chronic exposure in adults include headache, stomach-ache, memory loss, renal failure, sexual dysfunction, and reduced sensation in the limbs [1]. These symptoms manifest when the blood lead levels exceed 40 μg/dL in adults and 60 μg/dL in children [1]. According to Centers for Disease Control and Prevention (CDC), the lethal oral dose (immediately dangerous to life or health concentrations) of Pb is 450 mg/kgbw (milligrams per kilogram of body weight) [4].

The management of lead exposure is controlled by chelating agents [5]. Chelation agents specifications include (i) high binding affinity to the metal, (ii) low toxicity, (iii) penetration of the tissues where they accumulate and (iv) rapid removal from the body (water solubility of the metal agent complex), preferably via urine [5].

Penicillamine was the first tested antidote for lead detoxification, but its absorption was inhibited by food, antioxidants and iron supplements [1]. The role of N-acetylcysteine on excretion of Pb in rats has been examined and the results showed a dose-depended renal and facial excretion of bivalent lead, but not tetravalent [6]. The most used agents for lead detoxification are dimercaptopropanol (dimercaprol or BAL) and calcium disodium ethylene diamine tetraacetic acid (CaNa2EDTA) [7]. CaNa2EDTA is preferable than EDTA, in the case of lead displacement from bones [7]. The major disadvantage, however, of CaNa2EDTA, is its distribution exclusively in extracellular space, while Pb(II) accumulates intracellularly [7]. In addition, CaNa2EDTA is not effective in reducing the brain lead level [8]. Another drawback of the usage of BAL and CaNa2EDTA, as antidotes is the necessity of intramuscular administration several times per day for 5 to 7 days [7]. Regarding lead exposure, chelation therapy with CaNa2EDTA is recommended when the blood lead levels are 50–60 μg/dL. When the blood lead levels exceed the 70 μg/dL monotherapy with CaNa2EDTA worsen the symptoms [9]. Another antidote for lead detoxification is 2,3-Dimercaptosuccinic acid (DMSA). Its adverse effects include a rise in transaminase activity and skin reactions [10]. However, neither DMSA is capable of remove lead from intracellular sites or hard tissues [10]. In addition, it has been demonstrated that DMSA, its analogue 2,3-Dimercapto-1-propanesulfonic acid (DMPS), BAL and EDTA, as well as Pb, inhibit the enzyme participating in heme biosynthesis [11]. Moreover, the chelation therapy with the prementioned agents induce adverse effects, such as fever, nausea, headache, vomiting, high/low blood pressure, gastrointestinal distress, muscle pain, pain at the site of the injection and burning sensation [8]. Other reported natural detoxification systems include cyclic octapeptides composed of glutathione and binding groups such as thiols, carboxylic acids, and imidazoles [12,13], which were tested them for their ability to recover Pb-poisoned human cells [12,13]. These peptides were found to be highly selective for Pb(II) ions over Ca(II) [12,13].

Salicylic acid (SalH) (Scheme1) and its derivatives are used as drugs [14]. They have been employed for the treatment of various diseases, as they reduce fever and inflammation, promote analgesia and prevent clotting [14]. SalH is also used as preservative agent in food industry [14]. Salicylate content has been found in vegetables, fruits, meat and dairy products, cereal and drinks [15]. Methyl salicylate is a flavouring for foods, candies, beverages and pharmaceuticals [14]. SalH has also been used in cosmetic as denaturant, hair-conditioning and skin-conditioning agent [16]. Moreover, the role of SalH in the plant detoxification has been examined, thoroughly [17]. SalH is a significant regulator of biochemical processes in plants, including plant signalling, plant defence and response to heavy metals [17]. However, the widespread availability, ease of access, and frequent co-ingestion of multiple salicylate-containing agents, combined with the nonlinear pharmacokinetic properties of salicylate, make salicylism a common and sometimes fatal occurrence [18]. Since water solubility is prerequired for an antidote and due to the very slight solubility of SalH in water, its potassium salt (SalK) instead of the sodium one or the salicylic acid itself, was used. This is because the KOH is stronger base than NaOH as the ionization energy of Na is 495.8 kj/mol vs K has 418.8 kj/mol, which makes K more reactive than Na.

In the course of our studies on the mechanism of heavy metal ions detoxification [[19], [20], [21], [22]], we report here the formation of a Pb coordination polymer with formula (SaLead) with salicylic acid (SalH, Scheme 1). The compound has been characterized by melting point, Attenuated Total Reflectance-Fourier Transform Infra-Red (ATR-FTIR) and Ultra Violet (UV) spectroscopies and X-ray diffraction crystallography (XRD). The genotoxicity of SaLead was in vitro and in vivo tested.

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