Antidotes enzymes

Enzymes as Antidotes. Rhodanese [9026-04-4] given along with thiosulfate to counteract cyanide poisoning in mice (224) was the first enzyme used as an antidote. This combination raised the LD q of potassium cyanide in mice by eightfold (224). 

Methotrexate (MTX, chemical structure shown in Fig. 1.) competitively inhibits the dehyrofolate reductase, an enzyme that plays an essential role in purine synthesis. The dehydrofolate reductase regenerates reduced folates when thymidine monophosphate is formed from deoxyuridine monophosphate. Without reduced folates cells are unable to synthesize thymine. Administration of N-5 tetrahydrofolate or N-5 formyl-tetrahydrofolate (folinic acid) can bypass this block and rescue cells from methotrexate activity by serving as antidote. 

CBs, like OPs, act as inhibitors of ChE. They are treated as substrates by the enzyme and carbamylate the serine of the active site (Figure 10.8). Speaking generally, car-bamylated AChE reactivates more rapidly than phosphorylated AChE. After aging has occurred, phosphorylation of the enzyme is effectively irreversible (see Section 10.2.4). Carbamylated AChE reactivates when preparations are diluted with water, a process that is accelerated in the presence of acetylcholine, which competes as a substrate. Thus, the measurement of AChE inhibition is complicated by the fact that reactivation occurs during the course of the assay. Carbamylated AChE is not reactivated by PAM and related compounds that are used as antidotes to OP poisoning (see Box 10.1). 

Another disadvantage of the first generation reactivators lies in their lacking of antidotic effect in respect to affections induced by soman, which causes fast aging of the phosphorylated enzyme. 

These potent natural toxins are tasteless and odorless, and contaminated seafood appears to be completely normal. They are not destroyed by cooking or by food preservation (e.g., freezing, drying, or salting). In addition, these toxins are refractory to the action of human digestive enzymes, and there are no antidotes against their biological activity (Schantz, 1973). 

AChE and direct the oximate anion toward the P atom, proved to be extremely efficient in terms of rate of displacement of the enzyme-bound phosphoryl group (i.e. reactivation) and, consequently, as an antidote. The pioneering work of Wilson and colleagues in the early 1950s served as the scientific foundation for the synthesis and evaluation of more than 1000 oxime-containing reactivators over the past 50 years, that have been described in hundreds of pubhcations. 2-PAM and several bis-quatemary oximes 39 , 40 and... 

Cyanide poisoning poses some risk however, this is minimized both by the kinetic inertness of both Fe and Fe " cyano complexes and the high affinity of these ions for cyanide ([Fe"(CN)6] , fi6 10 [Fe "(CN)6] , Bg 10 [7, 35]. Small amounts of cyanide, which are released by photolysis and reduction products of nitroprusside, can usually be metabolized in the liver and kidneys by the enzyme rhodanase, which converts CN" to SCN [7, 36]. Cyanide can also be taken up by hydroxocobalamin to generate cy-anocobalamin (B12). As the conversion of cyanide to thiocyanate is dependent on the availability of sulfur, thiosulfate can be administered as an antidote [37]. Monitoring thiocyanate levels as an indicator of cyanide toxicity is no longer routine, but is done on patients with severe hepatic compromise who have been... 

The first suggestion of a practical form of antidotal therapy came in 1949 from Hestrin, who found that acetylcholinesterase (AChE) catalyzed the formation of acetohydroxamlc acid when incubated with sodium acetate and hydroxylamine. Critical in vitro studies in the next decade led to the development of a practical approach to therapy. The crucial concept in these studies was the recognition that the compound formed when AChE reacted with a phosphorus ester was a covalent phosphoryl-enzyme Intermediate similar to that formed in the hydrolysis of acetylcholine. 3 Wilson and colleagues, beginning in 1951, demonstrated that AChE inhibited by alkyl phosphate esters (tetraethyl pyrophosphate, TEPP) could be reactivated by water, but that free enzyme formed much more rapidly in the presence of hydroxylamine. 0 21 Similar results... 

Chelating agents are widely used as specific antidotes for heavy metals. They form stable, soluble, nontoxic complexes and in easily excreted form. They promote dissociation of bound metal from tissue enzymes and other functional macromolecules. These metal chelates are water soluble, e.g. EDTA, BAL, desferrioxamine etc. 

It is used as leucovorin calcium (calcium folinate). It is 5-formyl derivative of tetrahydrofolic acid and it acts as an antidote to folic acid antagonists like methotrexate or pyrimethamine which inhibit the enzyme dihydrofolate reductase. 

Metabolism of ethylene glycol and methanol to their toxic products can be blocked by inhibiting the enzyme alcohol dehydrogenase with a competing drug, such as fomepizole (4-methylpyrazole). Ethanol is also an effective antidote, but it can be difficult to achieve a safe and effective blood level. 

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