The organotellurium compound ammonium trichloro(dioxoethylene‐o,o′)tellurate reacts with homocysteine to form homocystine and decreases homocysteine levels in hyperhomocysteinemic mice

Abstract

Homocysteine is a thiol-containing amino acid synthesized in mammals ⁄ humans as part of the normal metabolism of the essential amino acid methionine. Studies conducted over the past three decades have shown that high levels of homocysteine in the plasma (hyperhomocysteinemia, i.e. > 15 lmolAEL ) constitute a risk factor for cardiovascular diseases and stroke [1]. Elevated homocysteine is also a risk factor for several neurodegenerative disorders, such as dementia [2], Alzheimer's disease [3], and Parkinson's disease [4]. As elevated homocysteine is associated with an increasing number of pathologies, the regulation of homocysteine levels is of clinical importance.Several factors contribute to elevated homocysteine levels: (a) genetic disorders stemming from mutations in the enzymes involved in homocysteine remethylation to methionine (e.g. 5,10-methylenetetrahydrofolate reductase) [ Ammonium trichloro(dioxoethylene-o,o¢)tellurate (AS101) is an organotellurium compound with pleiotropic functions that has been associated with antitumoral, immunomodulatory and antineurodegenerative activities. Tellurium compounds with a +4 oxidation state, such as AS101, react uniquely with thiols, forming disulfide molecules. In light of this, we tested whether AS101 can react with the amino acid homocysteine both in vitro and in vivo. AS101 conferred protection against homocysteine-induced apoptosis of HL-60 cells. The protective mechanism of AS101 against homocysteine toxicity was directly mediated by its chemical reactivity, whereby AS101 reacted with homocysteine to form homocystine, the less toxic disulfide form of homocysteine. Moreover, AS101 was shown here to reduce the levels of total homocysteine in an in vivo model of hyperhomocysteinemia. As a result, AS101 also prevented sperm cells from undergoing homocysteine-induced DNA fragmentation. Taken together, our results suggest that the organotellurium compound AS101 may be of clinical value in reducing total circulatory homocysteine levels.Abbreviations AS101, ammonium trichloro(dioxoethylene-o,o¢)tellurate; ddw, double-deionized water; DEVD, Ac-benzyloxycarbonyl aspartyl glutamylvalylaspartic acid; DFI, DNA fragmentation index; FACS, fluorescence-activated cell sorter; Nbs 2 , 5,5¢-dithiobis(2-nitrobenzoic acid); PI, propidium iodide; pNA, p-nitroaniline; RP, reaction product; SCSA, sperm chromatin structure assay.

The anti-inflammatory effects of the tellurium redox modulating compound, AS101, are associated with regulation of NFκB signaling pathway and nitric oxide induction in macrophages

“…Furthermore, the proteolytic activity of the inactivated cysteine proteases could be restored by reducing agents further supporting the suggestion that the inactivation process involves oxidation of the catalytic thiol to a disulfide[14]. Furthermore, neuroprotection exerted by AS101 in both Parkinson's disease models[16] and ischemic stroke[25] were shown to be mediated by the Te(IV) redox chemistry of the compound. Likewise, the protective mechanism of AS101 against homocysteine toxicity was shown to be directly mediated by its chemical reactivity, whereby AS101 reacted with homocysteine to form homocystine, the less toxic disulfide form of homocysteine[25].…”

“…Furthermore, neuroprotection exerted by AS101 in both Parkinson's disease models[16] and ischemic stroke[25] were shown to be mediated by the Te(IV) redox chemistry of the compound. Likewise, the protective mechanism of AS101 against homocysteine toxicity was shown to be directly mediated by its chemical reactivity, whereby AS101 reacted with homocysteine to form homocystine, the less toxic disulfide form of homocysteine[25]. These marked redox potential of AS101 may account for the aforementioned anti-inflammatory effects of the compound.…”

The organotelluride catalyst LAB027 prevents colon cancer growth in the mice

“…In addition, AS101, as a tellurium (IV) compound, can interact with thiols to form a Te-S bond. The ability of AS101 to interact with cysteine residue can alter protein functions, 38 increase intracellular ROS and favor the induction of apoptosis. 39 However, all the activities of AS101 are associated with little toxicity, and this drug is safe for clinical applications.…”

Redox Modulation of Adjacent Thiols in VLA-4 by AS101 Converts Myeloid Leukemia Cells from a Drug-Resistant to Drug-Sensitive State

“…Many of the beneficial effects of AS101 were shown to be attributed to redox modulation by the compound (20)(21)(22). The following experiments show that the VLA-4 integrin activity on AML cells can be regulated by vicinal thiols redox rearrangements and that this mechanism of action exerted by AS101 has physiologic consequences both in vitro and in vivo.…”

“…Indeed, we demonstrated that the specific redox-modulating activities of AS101 result in a variety of beneficial biologic effects: inhibition of interleukin (IL)-10 (20) resulting in tumor sensitization (18); neuroprotection in both Parkinson disease models (20); and ischemic stroke (21), all mediated by the Te(IV) redox chemistry of the compound. Likewise, the protective mechanism of AS101 against homocysteine toxicity was shown to be directly mediated by its chemical reactivity, whereby AS101 reacted with homocysteine to form homocystine, the less toxic disulfide form of homocysteine (22).…”