Detoxification process

Care should be exercised when attempting to interpret in vivo pharmacological data in terms of specific chemical—biological interactions for a series of asymmetric compounds, particularly when this interaction is the only parameter considered in the analysis (10). It is important to recognize that the observed difference in activity between optical antipodes is not simply a result of the association of the compound with an enzyme or receptor target. Enantiomers differ in absorption rates across membranes, especially where active transport mechanisms are involved (11). They bind with different affinities to plasma proteins (12) and undergo alternative metaboHc and detoxification processes (13). This ultimately leads to one enantiomer being more available to produce a therapeutic effect. 

The process of reabsorption depends on the HpophiHc—hydrophiHc balance of the molecule. Charged and ioni2ed molecules are reabsorbed slowly or not at all. Reabsorption of acidic and basic metaboHtes is pH-dependent, an important property in detoxification processes in dmg poisoning. Both passive and active carrier-mediated mechanisms contribute to tubular dmg reabsorption. The process of active tubular secretion handles a number of organic anions and cations, including uric acid, histamine, and choline. Dmg metaboHtes such as glucuronides and organic acids such as penicillin are handled by this process. 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

Metabolic pathways containing dioxygenases in wild-type strains are usually related to detoxification processes upon conversion of aromatic xenobiotics to phenols and catechols, which are more readily excreted. Within such pathways, the intermediate chiral cis-diol is rearomatized by a dihydrodiol-dehydrogenase. While this mild route to catechols is also exploited synthetically [221], the chirality is lost. In the context of asymmetric synthesis, such further biotransformations have to be prevented, which was initially realized by using mutant strains deficient in enzymes responsible for the rearomatization. Today, several dioxygenases with complementary substrate profiles are available, as outlined in Table 9.6. Considering the delicate architecture of these enzyme complexes, recombinant whole-cell-mediated biotransformations are the only option for such conversions. E. coli is preferably used as host and fermentation protocols have been optimized [222,223]. 

Pool concentration of a substance that exceeds the threshold - for example megadose vitamin C - or substances that are excreted unchanged because they cannot be metabolised, such as sugar alcohols, or compounds that are not biologically essential, such as carcinogens, bacterial toxins and some minor plant constituents, are also bioavailable (and thus bioactive) in that they have a metabolic impact, even if this is only the stimulation of detoxification processes, or the use of energy for their excretion. 

Caurant F, Navarro M, Amiard JC. 1996. Mercury in pilot whales possible limits to the detoxification process. Sci Total Environ 186 95-104. 

Adsorption is a physicochemical process whereby ionic and nonionic solutes become concentrated from solution at solid-liquid interfaces.3132 Adsorption and desorption are caused by interactions between and among molecules in solution and those in the structure of solid surfaces. Adsorption is a major mechanism affecting the mobility of heavy metals and toxic organic substances and is thus a major consideration when assessing transport. Because adsorption is usually fully or partly reversible (desorption), only rarely can it be considered a detoxification process for fate-assessment purposes. Although adsorption does not directly affect the toxicity of a substance, the substance may be rendered nontoxic by concurrent transformation processes such as hydrolysis and biodegradation. Many chemical and physical properties of both aqueous and solid phases affect adsorption, and the physical chemistry of the process itself is complex. For example, adsorption of one ion may result in desorption of another ion (known as ion exchange). 

The role of N-sulfonyloxy arylamines as ultimate carcinogens appears to be limited. For N-hydroxy-2-naphthylamine, conversion by rat hepatic sulfotransferase to a N-sulfonyloxy metabolite results primarily in decomposition to 2-amino-l-naphthol and 1-sulfonyloxy-2-naphthylamine which are also major urinary metabolites and reaction with added nucleophiles is very low, which suggests an overall detoxification process (9,17). However, for 4-aminoazobenzene and N-hydroxy-AAF, which are potent hepatocarcinogens in the newborn mouse, evidence has been presented that strongly implicates their N-sulfonyloxy arylamine esters as ultimate hepatocarcinogens in this species (10,104). This includes the inhibition of arylamine-DNA adduct formation and tumorigenesis by the sulfotransferase inhibitor pentachlorophenol, the reduced tumor incidence in brachymorphic mice that are deficient in PAPS biosynthesis (10,115), and the relatively low O-acetyltransferase activity of mouse liver for N-hydroxy-4-aminoazobenzene and N-OH-AF (7,114,115). 

Bacteria possess biological efflux pumps that involve an energy-dependent export of antibiotics, among other substances, from within either the periplasm or cytoplasm to the outside environment. This is essentially a detoxification process for the bacteria. The phenomenon decreases the concentration of antibiotic inside the cell [7]. 

The liver is the dominant organ in the detoxification process. The detoxification occurs by biotransformation, in which the chemical agents are transformed by reaction into either harmless or less harmful substances. Biotransformation reactions can also occur in the blood, intestinal tract wall, skin, kidneys, and other organs. 

Dillon AP. 1981. Disposal of selected pesticides. In Pesticide disposal and detoxification processes and techniques. Noyes Data Corporation, Park Ridge, NJ. 

The polymerization of phenols or aromatic amines is applied in resin manufacture and the removal of phenols from waste water. Polymers produced by HRP-catalyzed coupling of phenols in non-aqueous media are potential substitutes for phenol-formaldehyde resins [123,124], and the polymerized aromatic amines find applications as conductive polymers [112]. Phenols and their resins are pollutants in aqueous effluents derived from coal conversion, paper-making, production of semiconductor chips, and the manufacture of resins and plastics. Their transformation by peroxidase and hydrogen peroxide constitutes a convenient, mild and environmentally acceptable detoxification process [125-127]. 

The biochemical roles of these processes The metabolism of glutamate and aspartate by the enterocytes provides not only ATP, via oxidation of the oxoacids, but can also be considered to be a detoxification process. Both glutamate and aspartate are neurotransmitters in the brain. If their concentrations in blood increase too much, they could interfere with the control of neurotransmitter levels in the brain with possible changes in behaviour or clinical problems (see below). One such phenomenon is Chinese Restaurant Syndrome , but there may be other problems, as yet not reparted. 

Dillon, A.P. Pesticide Disposal and Detoxification Processes and Techniques Noyes Data Corporation Park Ridge, NJ, 1981. 

Iron(n) is known to decompose hydrogen and dialkyl peroxides to free radicals by reductive cleavage of the 0—0 bond and early investigations established the parasite s sensitivity to these species. When treated with radiolabelled C-artemisinin, the hemin-hemozoin fraction of the lysed malaria-infected erythrocytes was shown to contain a radiolabel, though the mechanism of incorporation is not clear. Meshnick and coworkers demonstrated that uninfected cells did not contain radiolabelled proteins whereas six radiolabelled proteins were isolated from cells infected with the Plasmodium falciparum (P. falciparum) strain of the parasite. It was suspected that one of the alkylated proteins was the Histidine Rich Protein (HRP) that was known to bind multiple heme monomers and therefore thought to be instrumental to the parasite s detoxification process. Moreover, iron chelators were found to inhibit the lethal effects of peroxides on the parasite. ... 

The a-thioalkyl trifluoromethyl ketones are also selective inhibitors of mammalian carboxyesterases. These enzymes are involved in the liver detoxification processes. ... 

IT Corporation (IT) developed a two-stage photolytic and biological soil detoxification process to treat soils contaminated with polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-/7-dioxin (TCDD). The photolysis/biodegradation process has been evaluated under the U.S. 

Phase I metabolic reactions involve oxidation, reduction, or hydrolysis of the parent molecule, resulting in the formation of a more polar compound. Phase 1 reactions are mediated by the cytochrome P450 (GYP) family of enzymes. While metabolism used to be thought of as the body s detoxification process, phase I metabolites may be equally or even more pharmacologically active than the parent compound. Drug metabolism in general, and CYP-based mechanisms in particular, are discussed in detail in Chapter 5. 

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