Metabolism toxic metabolites

Methoxyflurane (Fig. 18.6) is seldom used beoause of its propensity to cause renal toxicity. It is the most potent of the agents discussed here, and it has the highest solubility in blood. Induotion and recovery would be expected to be slow. Chemically, it is rather unstable, and as much as 50% of an administered dose can be metabolized. Toxic metabolites significantly limit its utility as a general anesthetic (Fig. 18.7). 

ADH also has clinical significance in the metabolism of methanol and ethylene glycol, two drugs with toxic metabolites. Methanol is oxidized by ADH to formaldehyde, which damages the retina and can cause blindness. Ethylene glycol is metabohzed by ADH to oxalic acid, which has renal tox-... 

Practically all toxicokinetic properties reported are based on the results from acute exposure studies. Generally, no information was available regarding intermediate or chronic exposure to methyl parathion. Because methyl parathion is an enzyme inhibitor, the kinetics of metabolism during chronic exposure could differ from those seen during acute exposure. Similarly, excretion kinetics may differ with time. Thus, additional studies on the distribution, metabolism, and excretion of methyl parathion and its toxic metabolite, methyl paraoxon, during intermediate and chronic exposure are needed to assess the potential for toxicity following longer-duration exposures. 

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) ... 

Disulfiram works by irreversibly blocking the enzyme aldehyde dehydrogenase, a step in the metabolism of alcohol, resulting in increased blood levels of the toxic metabolite acetaldehyde. As levels of acetaldehyde increase, the patient experiences decreased blood pressure, increased heart rate, chest pain, palpitations, dizziness, flushing, sweating, weakness, nausea and vomiting, headache, shortness of breath, blurred vision, and syncope. These effects are commonly referred to as the disulfiram-ethanol reaction. Their severity increases with the amount of alcohol that is consumed, and they may warrant emergency treatment. Disulfiram is contraindicated in patients who have cardiovascular or cerebrovascular disease, because the hypotensive effects of the disulfiram-alcohol reaction could be fatal in such patients or in combination with antihypertensive medications. Disulfiram is relatively contraindicated in patients with diabetes, hypothyroidism, epilepsy, liver disease, and kidney disease as well as impulsively suicidal patients. 

Bioremediation also has its limitations. Some chemicals are not amenable to biodegradation, for instance, heavy metals, radionuclides, and some chlorinated compounds. In some cases, the microbial metabolism of the contaminants may produce toxic metabolites. Bioremediation is a scientifically intensive procedure that must be tailored to site-specific conditions, and usually requires treatability studies to be conducted on a small scale before the actual cleanup of a site.13 The treatability procedure is important, as it establishes the extent of degradation and evaluates the potential use of a selected microorganism for bioremediation. A precise estimate on vessel size or area involved, speed of reaction, and economics can therefore be determined at the laboratory stage. 

Hepatic Effects. Acrylonitrile is metabolized in the liver to potentially toxic metabolites (see Section 2.3). There are limited indications that the liver is a target organ for acrylonitrile toxicity. 

Hansen, J.I., T. Mustafa, and M. Depledge. 1992b. Mechanisms of copper toxicity in the shore crab, Carcinus maenas. B. Effects on key metabolic enzymes, metabolites and energy charge potential. Mar. Biol. 114 259-264. 

Table 6.3 gives typical data for the metabolism of benzoic acid to its less toxic metabolite hippuric acid. 

This epoxidation of AFB has been associated with aldrin epoxidase (AE) activity in trout (30). As with other epoxide carcinogens, OAFB may be a substrate 7or epoxide metabolizing enzyme systems such as epoxide hydrase (EH) (EC4.2.1.63) and glutathione-S-epoxide transferase (GTr) (EC4.4.1.7) found in mammals and fish (31, 32, 33, 34). AFB also undergoes a variety of other reactions, generally to less toxic metabolites depending on the species of animal involved (35, 36). The primary AFB metabolite in rainbow trout has been shown to be a reduced form of AFB, aflatoxicol (AFL) (24). 

The hepatic injury caused by iproniazid could also be due to the formation of the toxic metabolite hydrazine by A-dealkylation followed by hydrolysis. Indeed, A-dealkylation is a main route in the metabolism of iproniazid, with plasma levels of hydrazine in rabbits three- to sixfold higher than after isoniazid [188],... 

Bromoethylamine (11.133, R = Br, Fig. 11.18) is a potent nephrotoxin used to create an experimental model of nephropathy. Its mechanism of toxicity is postulated to involve perturbation of mitochondrial function, and its metabolism was investigated in a search for toxic metabolites. In rat plasma, 2-bromoethylamine was converted to aziridine (11.134), formed by intramolecular nucleophilic substitution and bromide elimination [155], Another major metabolite was oxazolidin-2-one (11.136). This peculiar metabolite resulted from the reaction of 2-bromoethylamine with endogenous carbonate to form carbamic acid 11.135, followed by cyclization-elimination to oxazoli-din-2-one. In aqueous media containing excess carbonate, the formation of... 

With the advent of modern LC/MS instrumentation and sophisticated software, metabolic profiling has gradually become a significant tool to support drug discovery. Early identification of active or toxic metabolites and characterization of metabolic liability of a particular structural series will significantly reduce the cycle time of the lead opti-... 

In addition to the above examples, toxicity problems can also arise when one drug induces the metabolism of the second drug. Toxic metabolites, which are not normally present in a sufficiently high concentration to be noticeable, may increase due to the increase in their concentration as a... 

Glutathione is also implicated in the removal of toxic metabolites from the analgesic paracetamol (USA acetaminophen). Oxidative metabolism of paracetamol produces an A-hydroxy derivative, and this readily loses water to generate a reactive and toxic quinone imine, which interacts with proteins to cause cell damage. 

The chemical strucmre of a substance may contain strucmral alerts for reproductive toxicity, based on clear evidence for reproductive toxicity of strucmral analogues. For example, glycol ethers, which are metabolized to a reproductive toxic metabolite (an oxyacetic acid) should be considered as reproductive toxicants unless data are available showing no reproductive toxicity of the substance under evaluation. 

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