Oximes as inhibitors of low density lipoprotein oxidation

Portella, Rafael de Lima; Barcelos, Raquel Cristine Silva; de, Andreza Fabro; Carratu, Vanessa Santana; Bresolin, Leandro; Rocha, João Batista Teixeira da; Soares, Félix Alexandre Antunes

doi:10.1016/j.lfs.2008.10.005

Cited by 13 publications

(6 citation statements)

References 70 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We compared the effects of two classical oximes (pralidoxime and obidoxime) and two newly synthesised oximes in protecting or reactivating methamidophos‐inhibited cholinesterases. The two newly synthesised oximes had previously been found to be related with a protective effect on LDL oxidation and have shown no signs of toxicity during in vivo or ex vivo use . In addition, these new oximes have been found to have LD 50 values similar to other oximes, including pralidoxime and obidoxime .…”

Section: Discussionmentioning

confidence: 81%

Effect of Different Oximes on Rat and Human Cholinesterases Inhibited by Methamidophos: A Comparative In Vitro and In Silico Study

Lugokenski

Gubert

Bueno

et al. 2012

Basic Clin Pharma Tox

Self Cite

View full text Add to dashboard Cite

Methamidophos is one of the most toxic organophosphorus (OP) compounds. It acts via phosphorylation of a serine residue in the active site of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), leading to enzyme inactivation. Different oximes have been developed to reverse this inhibition. Thus, our work aimed to test the protective or reactivation capability of pralidoxime and obidoxime, as well as two new oximes synthesised in our laboratory, on human and rat cholinesterases inhibited by methamidophos. In addition, we performed molecular docking studies in non-aged methamidophos-inhibited AChE to understand the mechanisms involved. Our results suggested that pralidoxime protected and reactivated methamidophos-inhibited rat brain AChE. Regarding human erythrocyte AChE, all oximes tested protected and reactivated the enzyme, with the best reactivation index observed at the concentration of 50 lM. Concerning BChE, butane-2,3-dionethiosemicarbazone oxime (oxime 1) was able to protect and reactivate the methamidophos-inhibited BChE by 45% at 50 lM, whereas 2(3-(phenylhydrazono) butan-2-one oxime (oxime 2) reactivated 28% of BChE activity at 100 lM. The two classical oximes failed to reactivate BChE. The molecular docking study demonstrated that pralidoxime appears to be better positioned in the active site to attack the O-P moiety of the inhibited enzyme, being near the oxyanion hole, whereas our new oximes were stably positioned in the active site in a manner similar to that of obidoxime. In conclusion, our work demonstrated that the newly synthesised oximes were able to reactivate not only human erythrocyte AChE but also human plasma BChE, which could represent an advantage in the treatment of OP compounds poisoning. Acetylcholinesterase (EC 3.1.1.7, AChE) is an enzyme that catalyses the hydrolysis of acetylcholine to choline and acetate. The biological function of this enzyme is to terminate acetylcholine activity in the terminal nervous junction with its effector organs or post-synaptic sites [1]. The mechanism of action of organophosphorus (OP) compounds with anticholin-esterase activity involves the phosphorylation of the serine hydroxyl group in the active site of AChE, leading to an inactive enzyme (AChE-OP) [2]. The inactivation of AChE results in the accumulation of acetylcholine at cholinergic receptor sites, causing a cholinergic crisis that can lead to death [3]. Methamidophos is a potent AChE inhibitor used to control plague of insects on a variety of crops [4] and may present anticholinesterase activity against human cholinesterases [5,6]. In Brazil in particular, methamidophos is commonly used on many crops, including cotton, soybeans and wheat, resulting in food [7] and occupational exposure [8]. A recent study demonstrated that over 90% of small farmers use methamido-phos and nearly 60% of them exhibit typical OP intoxication symptoms [9]. Mechanistically, methamidophos may inhibit AChE by covalently binding a serine residue (Ser203) in the active site, and this moiety could form two dif...

show abstract

Section: Discussionmentioning

confidence: 81%

Effect of Different Oximes on Rat and Human Cholinesterases Inhibited by Methamidophos: A Comparative In Vitro and In Silico Study

Lugokenski

Gubert

Bueno

et al. 2012

Basic Clin Pharma Tox

Self Cite

View full text Add to dashboard Cite

show abstract

“…Oximes have also been documented to decrease oxidation stress. 35) Pralidoxime has been reported to inhibit Na ϩ /Ca 2ϩ type I (cardiac type) exchanger and to decrease the intracellular calcium accumulation. 36,37) Na ϩ /Ca 2ϩ exchanger, a bi-directional ion transporter is an important regulator of intracellular calcium levels.…”

Section: Discussionmentioning

confidence: 99%

Ameliorative Potential of Pralidoxime in Tibial and Sural Nerve Transection-Induced Neuropathic Pain in Rats

Kaur

Jaggi

Singh

2010

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

The present study was designed to investigate the ameliorative potential of pralidoxime in tibial and sural nerve transection-induced neuropathy in rats. Tibial and sural nerve transection was performed by sectioning tibial and sural nerve portions (2 mm) of the sciatic nerve, and leaving the common peroneal nerve intact. The pinprick, acetone, hot and cold tail immersion tests were performed to assess the degree of motor functions, mechanical hyperalgesia, cold allodynia, heat and cold hyperalgesia respectively. Biochemically, the tissue thio-barbituric acid reactive species (TBARS), super-oxide anion contents (the markers of oxidative stress) and total calcium levels were measured. Tibial sural nerve transection resulted in the development of mechanical hyperalgesia, cold allodynia, heat and cold hyperalgesia along with the rise in oxidative stress and calcium levels. However, administration of pralidoxime (10, 20 mg/kg intraperitoneally (i.p.)) for 14 d attenuated tibial and sural nerve transection-induced cold allodynia, mechanical, hot and cold hyperalgesia. Furthermore, pralidoxime also attenuated tibial and sural nerve transection induced increase in oxidative stress and calcium levels. It may be concluded that pralidoxime has ameliorative potential in attenuating the painful neuropathic state associated with tibial and sural nerve transection, which may possibly be attributed to decrease in oxidative stress and calcium levels.

show abstract

“…Searching for modifications caused by IBTC in the protein moieties of LDL, we observed that IBTC prevented the Cu 2+ -induced loss of Trp fluorescence in LDL. Intrinsic ApoB-100 fluorescence has been widely used to monitor protein oxidative damage in Cu 2+ -induced oxidized LDL (de Lima Portella et al, 2008;Giessauf et al, 1995). It has been reported that the fluorescence spectrum of native LDL is associated with Trp residues in apo-B, and Trp fluorescence is a marker for oxidation occurring at the protein core of LDL (Reyftmann et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the IBTC protection from serum oxidation was greater than the protection from LDL oxidation. This result could be due in part to the presence of other antioxidants in plasma/serum (de Lima Portella et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…A possible method to prevent atherosclerotic diseases would be through the administration of antioxidants (de Lima Portella et al, 2008). However, there is some controversy regarding the usefulness of antioxidant therapy for the prevention of atherosclerosis (Mashima et al, 2001), and this reflects our limited understanding of the therapeutic use of antioxidants and the need for further studies.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation