Sulfonylureas toxicity

A. Sulfonylureas. Toxicity depends on the agent and the total amount ingested. Toxicity may also occur owing to drug interactions, resulting in impaired elimination of the oral agent. 

Sulfonylureas. The hypoglycemic effect of sulfonylureas was first noted in the early 1940s when several patients died in hypoglycemic coma after testing glyprothia2ole, a synthetic sulfonamide used to treat typhoid. Chemical modifications which enhanced activity and lowered toxicity led to the development of the first-generation sulfonylureas. Carbutamide [339-43-5] the first commercial sulfonylurea, came onto the European... 

Tolbutamide. Tolbutamide (l-but5l-3-(p-tolylsulfonyl)urea), with mol wt 270.35, is known as Orinase. It is a white to off-white practically ododess crystalline powder having a slightly bitter taste, mp 126—132°C. It is practically insoluble in water, and soluble in alcohol and chloroform. The toxicity of tolbutamide appears to be low, and reactions are similar to those observed with other sulfonylureas. 

Monotherapy with sulfonylureas generally produce a 1.5% to 2% decline in HbAlc concentrations and a 60 to 70 mg/dL (3.33-3.89 mmol/L) reduction in FBG levels. Secondary failure with these drugs occurs at a rate of 5% to 7% per year as a result of continued pancreatic p-cell destruction. One limitation of sulfonylurea therapy is the inability of these products to stimulate insulin release from (1-cells at extremely high glucose levels, a phenomenon called glucose toxicity. 

In summary, the sulfonylureas are new herbicides which exhibit activity at extremely low rates of application and show very low mammalian toxicity. Exceptionally high activity is shown by compounds containing a benzene ring substituted in the ortho position, an unsubstituted sulfonylurea bridge, and a pyrimidine or triazine heterocycle substituted with methyl or methoxy groups. 

Sales of agricultural products were 600 million in 1984. Du Pont expects to double this amount by 1990. There are many new products in the pipeline. Several of these new products are weed killers based on sulfonylurea chemistry. This family of weed killers is characterized by very low toxicity to mammals and high herbicidal activity at very low application rates in the field—often less than an ounce per acre of cropland. 

Tolazamide, tolbutamide, chlorpropamide Older sulfonylureas, lower potency, greater toxicity rarely used ... 

Adverse effect Hypoglycemia due to sulfonylureas Dose-relation toxic effect Time-course time-independent Susceptibility factors disease (impaired liver or kidney function, alcoholism) drug interactions reduced food intake exercise... 

Adverse effect Hypoglycemia due to sulfonylureas Dose-relation toxic effect Time-course time-independent... 

The selective toxicity of sulfonylureas to certain weeds without damage to the cereal crop arises from their rapid metabolism in the crop plant to inactive compounds, whereas in sensitive weeds the metabolism is much slower. The very high herbicidal activity suggests a specific biochemical mode of action, which is concluded to be the inhibition of plant cell division. Sulfonylureas block the enzyme acetolacetate synthase (ALS), which catalyses the biosynthesis of the essential branched chain amino acids valine, leucine and isoleucine. 

Second, a key enzyme or receptor in the pathway should be identified as the target. It is best to select enzymes whose products are important for several functions in the species. Cellular response to such a metabolic blockade should also be considered (e.g., cascading effects). Often end-product limitation results in more metabolites entering the pathway. After sufficient substrate accumulation, catalysis may occur even in the presence of an inhibitor (10). However, accumulation of toxic intermediates would prevent tTTTs cellular response and lead to death. Again using sulfonylureas as an example, acetolactate synthase is a common enzyme in the pathway for two essential amino acids rather than just one. Also, inhibition of acetolactate synthase leads to high levels of a-ketobutyrate which is thought to have deleterious effects (11). 

This lowering of rates should work equally well with the newer generation of herbicides (e.g. sulfonylureas). There is far too much toxic carryover from a wheat field treated with 30 g/ha chlorsulfuron to allow cultivation of many crops, and many weeds remain suppressed. If all the weeds in wheat could be controlled by the carryover level remaining, then there would be no carryover the following year. This requires ascertaining why some weeds are more tolerant to the herbicide than others information not fully available. 

ALS is also inhibited by a number of compounds which are structurally unrelated to the sulfonylureas. These include two other classes of herbicides the imidazolinones (5) and the triazolopyrimidines (Hawkes, T.R. Howard, J.L. Pontin, S.E. In Herbicides and Plant Metabolism, in press). LaRossa et al. have speculated on why ALS is such an effective target for so many inhibitors (6). Blocking ALS leads to the buildup of the toxic substrate a-ketobutyrate. The elevated levels of this metabolite combined with the reduced levels of the branched chain amino acids appear to make the inhibition of ALS a particularly lethal event. 

The sulfonylurea herbicides are a new family of chemical compounds, some of which are selectively toxic to weeds but not to crops. The selectivity of the sulfonylureas results from their metabolism to non-toxic compounds by particular crops, but not by weeds. In addition to efficient weed control, the sulfonylurea herbicides provide environmentally desirable properties such as field use rates as low as two grams/hectare and very low toxicity to mammals. The high specificity of the herbicides for their molecular target contributes to both of these properties. In addition, the low toxicity to mammals results from their lack of the target enzyme for the herbicides. Sulfonylureas inhibit the enzyme acetolactate synthase (ALS), also known as acetohydroxyacid synthase (AHAS), which catalyzes the first common step in the biosynthesis of the branched chain amino acids leucine, isoleucine and valine. In mammals these are three of the essential amino acids which must be obtained through dietary intake because the biosynthetic pathway for the branched chain amino acids is not present. The prototype structure of a sulfonylurea herbicide is shown in Figure 1. 

ALS has also been shown to be inhibited by two other structurally unrelated classes of herbicides, the imidazolinones (8,9) and the triazolopyrimidines (10,11). It has been shown that the toxicity of the sulfonylurea herbicides to bacteria is due, in part, to the accumulation of an ALS substrate a-ketobutyrate, which is itself toxic. It has been suggested that the dual effects of the accumulation of a toxic substrate and the inability to synthesize isoleucine, leucine and valine make ALS a particularly good target for herbicides (12). 

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