Metabolism to toxic products

Pharmaca can also be converted metabolically to toxic products in mammals. Special attention must therefore be given to the study of the processes involved in biotoxification since an understanding of these processes may indicate how to avoid toxic action by correct molecular manipulation. 

A. In the first few hours after ingestion, methanol-intoxicated patients present with inebriation and gastritis. Acidosis is not usually present because metabolism to toxic products has not yet occurred. There may be a noticeable elevation in the osmolar gap (see p 32) an osmolar gap of as little as 10 mOsm/L is consistent with toxic concentrations of methanol. 

Examples of Synthesis Routes Inherently Safer Than Others As summarized by Bodor (1995), the ethyl ester of DDT is highly effective as a pesticide and is not as toxic. The ester is hydrolytically sensitive and metabolizes to nontoxic products. The deliberate introduction of a structure into the molecule which facilitates hydrolytic deactivation of the molecule to a safer form can be a key to creating a chemical product with the desired pesticide effects but without the undesired environmental effects. This technique is being used extensively in the pharmaceutical industry. It is applicable to other chemical industries as well. 

The first treatment for methanol poisoning, as in all critical poisoning situations, is support of respiration. There are three specific modalities of treatment for severe methanol poisoning suppression of metabolism by alcohol dehydrogenase to toxic products, hemodialysis to enhance removal of methanol and its toxic products, and alkalinization to counteract metabolic acidosis. 

Ethanol Higher affinity for alcohol dehydrogenase used to reduce metabolism of methanol and ethylene glycol to toxic products ... 

Carbon tetrachloride causes centrilobular liver necrosis and steatosis after acute exposure, and liver cirrhosis, liver tumors, and kidney damage after chronic administration. The mechanism underlying the acute toxicity to the liver involves metabolic activation by cytochrome P-450 to yield a free radical (trichloromethyl free radical). This reacts with unsaturated fatty acids in the membranes of organelles and leads to toxic products of lipid peroxidation including malondialdehyde and hydroxynonenal. This results in hepatocyte necrosis and inhibition of various metabolic processes including protein synthesis. The latter leads to steatosis as a result of inhibition of the synthesis of lipoproteins required for triglyceride export. 

In M. vanbaalenii PYR-1, an aromatic-ring dioxygenase produces cis-dihydrodiols from PAHs they have been identified (Heitkamp et al, 1988b Khan et al, 2001 Moody et al, 2001, 2004) but their toxicity has not yet been determined. The cA-dihydrodiols are further metabolized to other products whose toxicity also has not been examined, such as chrysene 4,5-dicarboxylic acid, 4-formylchrysene-5-carboxylic acid and 10-oxabenzo[fife/]chrysen-9-one (Schneider et al, 1996 Moody et al, 2004). 

Organophosphate insecticide cholinesterase inhibitor prodrug converted to malaoxon. Less toxic in mannnals and birds because metabolized to inactive products. 

Effects attributed to chlordane exposure include blood dyscrasia, hepatotoxicity, neurotoxicity, immunotoxicity and cancer. Possible mechanisms of toxicity relevant to all target organs include the ability of chlordane and its metabolites to bind irreversibly to cellular macromolecules, inducing cell death or disrupting normal cell function. In addition, chlordane may increase tissue production of superoxide, which can accelerate lipid peroxidation, disrupting the function of cellular and subcellular membranes. Chlordane induces its own metabolism to toxic intermediates, which may exacerbate its hepatotoxicity. This may involve suppression of hepatic mitochondrial energy metabolism. 

Because of their relatively complex organic structures, many were degraded/metabolized to multiple products which had different toxicity and dissipation characteristics, and analytical characteristics, from the parents. 

Alcohols Alcohols contain a single-OH group. Methanol (200 ppm) slowly produces toxic metabolites and has been associated with fatalities and injuries, vision impairment, and optic nerve injury. Ethanol (1,000 ppm) is quickly metabolized and converted to CO2 it is the least toxic of the alcohols. Propanol (200 ppm), metabolized to toxic by-products, is more toxic than ethanol, but less toxic than other alcohols. Alcohol has a depressant, not a stimulant effect on the central nervous system. Alcohols reduce brain and spinal cord activity. Exposures to extremely high doses can result in death by involuntary ceasing of the respiratory system. The Ever can also be a vulnerable target organ for alcohols. 

Lethal Synthesis. This is a process in which the toxic substance has a close stmctural similarity to normal substrates in biochemical reactions. As a result, the material may be incorporated into the biochemical pathway and metabolized to an abnormal and toxic product. A classic example is... 

Enterohepatic circulation can lead to toxic effects. For example, the drug chloramphenicol is metabolized to a conjugate that is excreted in bile by the rat. Once in the gut, the conjugate is broken down to release a phase 1 metabolite that undergoes further metabolism to yield toxic products. When these are reabsorbed, they can cause toxicity. The rabbit, by contrast, excretes chloramphenicol conjugates in urine, and there are no toxic effects at the dose rates in question. 

The signiflcance of toxic metabolites is important in diverse metabolic situations (a) when a pathway results in the synthesis of a toxic or inhibitory metabolite, and (b) when pathways for the metabolism of two (or more) analogous substrates supplied simultaneously are incompatible due to the production of a toxic metabolite by one of the substrates. A number of examples are provided to illustrate these possibilities that have achieved considerable attention in the context of the biodegradation of chlorinated aromatic compounds (further discussion is given in Chapter 9, Part 1) ... 

Many degraded/metabolized to products which had different toxicity and dissipation characteristics than the parents. 

Numerous factors, many of them poorly understood, are involved in the development of HE. In severe hepatic disease, systemic circulation bypasses the liver, so many of the substances normally metabolized by the liver remain in the systemic circulation and accumulate to toxic levels. In excess, these metabolic by-products, especially nitrogenous waste, cause alterations in central nervous system functioning.20... 

Solutions that contain sodium citrate/citric acid (Shohl s solution and Bicitra) provide 1 mEq/L (1 mmol/L) each of sodium and bicarbonate. Polycitra is a sodium/potassium citrate solution that provides 2 mEq/L (2 mmol/L) of bicarbonate, but contains 1 mEq/L (1 mmol/L) each of sodium and potassium, which can promote hyperkalemia in patients with severe CKD. The citrate portion of these preparations is metabolized in the liver to bicarbonate, while the citric acid portion is metabolized to C02 and water, increasing tolerability compared to sodium bicarbonate. Sodium retention is also decreased with these preparations. However, these products are liquid preparations, which may not be palatable to some patients. Citrate can also promote aluminum toxicity by augmenting aluminum absorption in the GI tract. 

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