Xenobiotics acceptors

With bilirubin as the acceptor substance, UDP-glucuronyltransferase is activated by aging (SIO, W7), by alkaline dialysis (H2), or by treatment with Triton X-100 (M16, P5, W8, W9, WIO), deoxycholate (V2) or digitonin (HIO, W7). Comparable maximum activities were found. Studies with xenobiotic acceptor substrates yielded the same conclusion (H13, L14, L15, V4, W 7). Very rapid and maximum activation of p-nitrophenol UDP-glucuronyltransferase was obtained at pH 9.8-10.5 (V4). Digitonin-activation of UDP-glucosyl- and UDP-xylosyltransfer-ase activities (both assayed with bilirubin as the acceptor substrate) has also been reported (F3). 

There are various pathways for free radical-mediated processes in microsomes. Microsomes can stimulate free radical oxidation of various substrates through the formation of superoxide and hydroxyl radicals (the latter in the presence of iron) or by the direct interaction of chain electron carriers with these compounds. One-electron reduction of numerous electron acceptors has been extensively studied in connection with the conversion of quinone drugs and xenobiotics in microsomes into reactive semiquinones, capable of inducing damaging effects in humans. (In 1980s, the microsomal reduction of anticancer anthracycline antibiotics and related compounds were studied in detail due to possible mechanism of their cardiotoxic activity and was discussed by us earlier [37], It has been shown that semiquinones of... 

BTEX bioremediation projects often focus on overcoming limitations to natural degradative processes associated with the insufficient supply of inorganic nutrients and electron acceptors. However, other limitations associated with the presence and expression of appropriate microbial catabolic capacities may also hinder the effectiveness of bioremediation. Thus, while subsurface addition of oxygen or nitrate has proven sufficient to remove BTEX below detection levels [134,145,292,315,316], it has been only marginally effective at some sites [6]. Sometimes, the concentration of a target BTEX compound fails to decrease below a threshold level even after years of continuous addition of nutrients and electron acceptors [317]. This phenomenon has also been observed for many other xenobiotic and natural substrates under various experimental conditions [327-332]. 

The chemical bum is the expression of a chemical ability to react between two molecules, a xenobiotic one and a biochemical tissues one. An acid can only affect the eye if it finds some chemical structures of basic nature in the cornea. It s the same for the attack of an oxidizing agent toward reducing cellular molecules. Generally speaking, in a chemical reaction, there is always a donor entity and an acceptor entity. For more details see Sect. 3.4.2. 

Many xenobiotics, including a wide variety of quinones and nitro compounds, will accept an electron from almost any redox flavoenzyme. The microsomal reduction of nitroaromatic compounds, quinones, quinone-imines, some azoaromatic compounds, paraquat, and tetrazolium salts is catalyzed by NADPH-cytochrome P-450 reductase [44], One-electron transfer to these electron acceptors has been proved to be obligatory in the case of quinone and nitro compounds, and is probably obligatory in other cases as well. Therefore, a reduction of an aromatic compound by NADPH-cytochrome P-450 reductase can probably be assumed to form a free radical metabolite. In contrast, free radical formation by reductive dehalogenation is totally cytochrome P-450-dependent, with the reductase being inactive. 

The mechanism by which xenobiotic alcohols or esters are converted to fatty acid esters has not been studied. They could be formed by the action of lyase enzymes in the presence of fatty acid glyceryl esters, as in the conversion of farnesol to farnesol fatty acid esters (150). Some lipolytic acyl hydrolase enzymes from plants readily catalyze the transfer of lipid-bound fatty acids to low MW alcohol acceptors (150.151) and enzymes of this class could be responsible for the occasional formation of fatty acid conjugates of xenobiotic alcohols. Mechanisms involving fatty acid acyl CoA, phospholipids, or direct esterification with fatty acids might also be involved (1 ). 

Activation of drugs to give toxic products is common. Apart from non-enzymatic activation (e.g., via autoxidation), activation by enzymatic one-electron oxidation or reduction frequently occurs. Several non-specific oxidases and reductases are encountered in mammalian tissues. Enzyme systems that have been studied in detail are peroxidases and microsomal oxidases and reductases. Xanthine oxidase also has received some attention. In many insta .ces the end products of the reaction are critically dependent upon the presence of oxygen in the system. This is because oxygen is an excellent electron acceptor, i.e., it can oxidize donor radicals, forming superoxide in the process. In this way a redox cycle is set up in which the xenobiotic substrate is recovered. The toxic effects of the xenobiotic often can be attributed to the oxidative stress arising from such a cycle. However, it seems that for some substrates, oxidative stress of this kind can be less damaging than anaerobic reduction. Anaerobic reduction can lead to formation of further reduced products with additional toxicity. 

Although glycine conjugates are the most commonly found metabolites, the specific amino acid acceptor depends on both the animal species and the chemical structure of the xenobiotic. Little is known about this conjugation pathway in parasites. A. suum,... 

M. expansa, H. diminuta and F. hepatica failed to form hippurate, the glycine conjugate of benzoic acid (8), although small amounts of this product were detected in M. benedeni (60). Given that several other amino acids besides glycine can often serve as acyl acceptors particularly in invertebrate species (3), additional studies are needed before concluding that amino acid conjugation is not a pathway of parasite xenobiotic metabolism. 

Methylation is an important reaction in the biosynthesis of endogenous compounds such as adrenaline and melatonin, in the inactivation of biogenic amines such as the catecholamines, serotonine and histamine, and in modulating the activities of macromolecules, such as proteins and nucleic acids. The number of xenobiotics that are methylated is comparatively modest, yet this reaction is seldom devoid of pharmacodynamic consequences (toxication or detoxication). Reactions of methylation imply the transfer of a methyl group from the onium-type cofactor S-adeno-sylmethionine (SAM) to the substrate by means of a methyltransferase. The activated methyl group from SAM is transferred to the acceptor molecules R — XH or RX, as shown in Fig. 31.30. 

The transfer of a sulfonate group from the donor compound 3 -phosphoadenosine 5 -phosphosulfate (PAPS) to an acceptor compound (such as TH, steroids,. .. but also xenobiotics) is catalyzed by a large family of enzymes called sulfotransferases, located in the cytoplasmic fraction of, e.g., liver cells. Unlike glucuronidation, sulfation does not facilitate the excretion ofTH, but interferes with the deio-dination process. Sulfated THs strongly facilitate the IRD activity of D1 while they inhibit the D2, D3 activity, and theORDofDl Moreno et al., 1994 VisserT. J., 1990). 

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