Detoxification xenobiotic

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]. 

Livingstone, D.R. (1985). Responses of the detoxification/toxication enzyme system of molluscs to organic pollutants and xenobiotics. Marine Pollution Bulletin 16, 158-164. 

The term detoxification is sometimes used for many of the reactions involved in the metabohsm of xenobiotics. However, the term is not always appropriate because, as mentioned above, in some cases the reactions to which xenobiotics are subject acmally increase their biologic activity and toxicity. 

Researchers focused on the metabolically competent human hepatoma cell line HepG2 as a model of human liver. HepG2 cells are a well-known hepatoma cell line that retains many of the morphological characteristics of liver parenchymal cells. This model is often used as a useful tool for HRA/ERA-oriented chemical risk assessment due to the expression of antioxidant and xenobiotic metabolizing enzymes (in particular phase I and phase II enzymes responsible for the bioactivation/detoxification of various xenobiotics) that can be induced or inhibited by dietary and non-dietary agents [28-30]. 

Virtually all organisms possess biotransformation or detoxification enzymes that convert lipophilic xenobiotics to water-soluble and excretable metabolites (Yu et al. 1995). In the metabolic process, PAHs are altered by Phase I metabolism into various products such as epoxides, phenols,... 

To date, 16 GST isozymes have been found in humans [48]. Studies of several cancer tissues have revealed the overexpression of different GST isozymes, with GST Pl-1 (GST Pi, GST ji) being the most predominant. For this reason, GST Pl-1 is regarded as a potential tumor marker [5,49-53]. The high expression levels of GST Pl-1 (up to 2.7% of the total cytosolic protein [52]), combined with its detoxification role against xenobiotics, make GST Pl-1 a major player responsible for drug resistance in patients undergoing anticancer chemotherapy [49]. 

The detoxification and excretion of xenobiotics (i.e., foreign compounds, including diet-derived allelochemicals) involve a suite of highly complex processes that allow an organism to respond to its internal and external chemical environments. Suchmetabolic resistance involves the biochemical transformation... 

The membrane-attached cytochrome P450 enzymes are involved in a significant fraction of events associated with drug metabolism. Most of the cytochrome P450 (CYP) catalyzed reactions lead to the detoxification of xenobiotics, by forming hydrophilic metabolites that can be readily excreted from the body. 

McFadden SA. 1996. Phenotypicvariation in xenobiotic metabolism and adverse environmental response Focus on sulfur-dependent detoxification pathways. Toxicology 111 43-65. 

Finally, and most importantly, esterases play an essential role in the biotransformation and detoxification of xenobiotic esters and amides, a major theme of this book. 

Phosphorothioates and phosphonothioates are of particular significance as insecticides. Schematically, it can be stated that these xenobiotics undergo activation by oxidative desulfuration, and detoxification by hydrolytic cleavage. Oxidative desulfuration transforms phosphorothioates and phosphonothioates to the corresponding oxon derivatives (see Chapt. 7 in [59]), which are highly toxic as potent inactivators of acetylcholinesterase [69]. This route of toxification can be competitive with and/or followed by cleavage reactions, which can be either hydrolytic or oxidative. 

But there is more to water than its role as solvent, since, like oxygen, it is also a reagent (as well as a product, but this aspect is irrelevant here) in innumerable biochemical reactions. This is the biochemical role of water, a double one, in fact. First and foremost, water is a reagent in innumerable lifesupporting reactions. Secondly, and like for oxygen, evolution has recruited water as a major player in the detoxification and elimination of xenobiotics. This biological function of water, we believe, is presented here for the first time in its full depth and breadth. 

Quinones and other xenobiotics are metabolized primarily in the liver, and the end products are water-soluble compoimds that are excreted from the body. The first step in metabolism is usually an oxidative process (phase I detoxification), after which further oxidation and conjugation can occur (phase II detoxification). Although those reactions normally yield easily excreted products, some steps in the metabolic pathway may generate metabolites that are more toxic than the parent comporuid. 

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