Metabolites toxic

Neither the mechanism by which benzene damages bone marrow nor its role in the leukemia process are well understood. It is generally beheved that the toxic factor(s) is a metaboHte of benzene (107). Benzene is oxidized in the fiver to phenol [108-95-2] as the primary metabolite with hydroquinone [123-31-9] catechol [120-80-9] muconic acid [505-70-4] and 1,2,4-trihydroxybenzene [533-73-3] as significant secondary metabolites (108). Although the identity of the actual toxic metabolite or combination of metabolites responsible for the hematological abnormalities is not known, evidence suggests that benzene oxide, hydroquinone, benzoquinone, or muconic acid derivatives are possibly the ultimate carcinogenic species (96,103,107—112). 

Alkylating Agents. Figure 2 Biotransformation of cyclophosphamide - formation of inactive ( ) and toxic ( metabolites. 

The blood-brain barrier (BBB) forms a physiological barrier between the central nervous system and the blood circulation. It consists of glial cells and a special species of endothelial cells, which form tight junctions between each other thereby inhibiting paracellular transport. In addition, the endothelial cells of the BBB express a variety of ABC-transporters to protect the brain tissue against toxic metabolites and xenobiotics. The BBB is permeable to water, glucose, sodium chloride and non-ionised lipid-soluble molecules but large molecules such as peptides as well as many polar substances do not readily permeate the battier. 

Cellular defense mechanisms against toxins (A multistep mechanism for elimination of toxic metabolites and xenobiotics. It involves various transport, oxidation, and conjugation steps.) are usually divided into several steps as it is visualized on Fig. 3. Organic anion transporting proteins (OATPs) are responsible for the cellular uptake of endogenous compounds and... 

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. 

Another toxic metabolite is ammonia. It is released by spontaneous decomposition of glutamine and to a far greater extend produced as a metabolite in... 

Distribution. Once inside the body, trichloroethylene is easily absorbed into and distributed through the circulatory system. The amount that is not absorbed initially on inhalation is expired unchanged (see Section 2.3.1.1). Absorption from the gastrointestinal tract often leads to a first pass through the liver, where toxic metabolites can form (see Section 2.3.3). Trichloroethylene and its metabolites may form adducts with blood proteins, and the metabolite glyoxylate may become incorporated into amino acids (Stevens et al. 1992), thus facilitating their distribution. The ability of these compounds to traverse membranes accounts for then-generalized systemic effects. 

Pre-exposure to the organophosphate diazinon at exposures half the LC50 values increased the LC50 value by a factor of about five for guppy (Poecilia reticulata), but had no effect on the value for zebra fish (Brachydanio rerio). This was consistent with the observation that during pre-exposure of guppy there was a marked inhibition in the synthesis of the toxic metabolites diazoxon and pyrimidinol, whereas this did not occur with zebra fish in which the toxicity was mediated primarily by the parent compound (Keizer et al. 1993). 

Distal fission Although substituted catechols generally undergo extradiol fission, this may produce toxic metabolites, and can be circumvented by regioselective 1,6-dioxygenation. This is rather uncommon but it has been observed in a number of degradations ... 

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) ... 

In later chapters, considerable weight is given to the environmental significance of biotransformation and the synthesis of toxic metabolites. It is particularly desirable, therefore, to direct effort to the identification of such metabolites. This may present a substantially greater challenge than that of quantifying the original substrate for several reasons ... 

Licht D, BK Ahring, E Arvin (1996) Effects of electron acceptors, reducing agents, and toxic metabolites on anaerobic degradation of heterocyclic compounds. Biodegradation 1 83-90. 

Evaluation of success is of primary importance. Loss of substrates is a necessary but not sufficient condition, in the light of the frequency of biotransformation reactions and the formation of terminal and possibly toxic metabolites. 

Toxic metabolites such as lactic acid and denatured proteins accumulate. The pH fells with accumulation of H" ions (Green and Pe, 1979). 

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