Detoxification of xenobiotics

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. 

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. 

The majority of the enzyme-catalyzed reactions discussed so far are oxidative ones. However, reductive electron transfer reactions take place as well. Diaphorase, xanteneoxidase, and other enzymes as well as intestinal flora, aquatic, and skin bacteria—all of them can act as electron donors. Another source of an electron is the superoxide ion. It arises after detoxification of xenobiotics, which are involved in the metabolic chain. Under the neutralizing influence of redox proteins, xenobiotics yield anion-radicals. Oxygen, which is inhaled with air, strips unpaired electrons from these anion-radicals and gives the superoxide ions (Mason and Chignell 1982). 

Ethanol can increase the levels of many enzymes involved in metabolism of xenobiotics. Prolonged ethanol intake causes irreversible damage in the central nervous system and in the liver, resulting in marked decreased capacity for detoxification of xenobiotics and thereby increased sensitivity to a number of chemicals (KEMI 2003). 

Despite the scarcity of direct evidence, HA is generally believed to be present as a metabolic intermediate in mammalian tissues Recent studies on the reductive detoxification of HAs both by human NADH-cytochrome i>5 reductase and by human cytochrome b5 may be considered as additional supporting evidence for the in vivo formation of HA in mammalian cells that needs to be controlled in order to avoid the toxic effects of an excess of endogenously produced HA, as well as of HA produced by detoxification of xenobiotic HA derivatives " . 

Two different enzyme systems have been described, one uses cytochrome P-450 to activate oxygen whereas the other employs flavin adenine dinucleotide (FAD). Both the cytochrome P-450 and the flavin monooxygenase systems have broad substrate specificities and oxidize and oxygenate a variety of organic nitrogen or sulfur compounds. The enzymes have a widespread distribution and have been detected in animals, plants, fungi and bacteria. Their function appears to be primarily one of detoxification of xenobiotics. Microbial enzymes... 

CYTOCHROME P-450 A family of heme-containing isozymes involved in the metabolic processing of thousands of substances, notably the toxification and detoxification of xenobiotics. (See also MONOOXYGENASES)... 

Modulation of liver and kidney function. Nutrients and xenobiotics (such as secondary metabolites) are transported to the liver after resorption in the intestine. In the liver, the metabolism of carbohydrates, amino acids, and lipids takes place with the subsequent synthesis of proteins and glycogen. The liver is also the main site for detoxification of xenobiotics. Lipophilic compounds, which are easily resorbed from the diet, are often hydroxylated and then conjugated with a polar, hydrophilic molecule, such as glucuronic acid, sulfate, or amino acids (312). These conjugates, which are more water soluble, are exported via the blood to the kidney, where they are transported into the urine for elimination. 

No populations unusually susceptible to 1,1-dichloroethane or chlorinated ethanes in general have been identified. NIOSH (1978) has identified thefollowing individuals as possibly being at increased risk from exposure to 1,1-dichloroethane (1) Individuals with skin disease because of the purported dermal irritant effects inducted by 1,1-dichloroethane. (2) Individuals with liver disease because of the role of this organ in the biotransformation and detoxification of xenobiotics such as... 

Mechanistic studies to examine the altered hepatotoxicity have traditionally focused on bioactivation/ detoxification of xenobiotics in diabetic state. Type 1 diabetes, at least in the streptozotocin-induced diabetic rat, increases several phase I drug metabolizing enzymes. However, changes in drug metabolizing enzymes differ depending on the species and... 

Knowles and Milner, 2000). Furthermore, these compounds are thought to be involved in the inhibition of certain cytochrome P-450 enzyme-dependent bioactivations of procarcinogens and protoxicants (Brady et al., 1991), as well as to increase levels of glutathione-S-transferase (GST), an enzyme of particular importance in the detoxification of xenobiotics in the body (Wilce and Parker, 1994). Most recently, the ability of various plants and plant extracts to influence apoptosis, or programmed cell death, in cancerous cells in an attempt to arrest their proliferation, has been the topic of much research. Allicin has been shown to induce apoptosis in a variety of cell lines, including human hepatocellular carcinoma cells (KIM-1) and human lymphoid leukemia (MOLT-4B) cells (Thatte et al., 2000). 

Glutathione (GSH) is one of the most important intracellular antioxidant molecules which serve to protect against ROS, as well as for detoxification of xenobiotics, removal of hydroperoxides, and maintenance of the cellular redox state. However, large quantities of ROS or reactive metabolites may lead to reduction/deple-tion of intracellular GSH level which will have deleterious consequences for the cell. GSH may be measured by monochlorbi-mane (mBCl), a lipophilic probe that passively diffuses across... 

Some of the functions of glutathione depend on the presence of the gamma-glutamyl bond, for instance its role in the regulation of amino acid transport. But the majority of the functions of glutathione are related to its role in redox regulation in cells and in detoxification of xenobiotics. 

Cytochrome P450 enzyme system The cytochromes P450 are mixed-function oxidases that require both NADPH and O. They are involved in a number of reactions in the conversion of lanosterol to cholesterol, as well as important steps in the synthesis of steroid hormones. Cytochromes P450 are very important in the detoxification of xenobiotics and in the metabolism of drags. 

Glutathione-transferase alpha (GST-a) protects cells by catalyzing the detoxification of xenobiotics and carcinogens. GST-a was recently found to be of diagnostic value in renal tumors. On the basis of cDNA microarray findings, immunohistochemical studies have so far shown GST-a to be highly expressed in CCRCC (90%) but not in ChRCC or oncocytomas and only occasionally in PRCC. 

The endoplasmic reticulum (ER) contributes to a variety of functions, including protein synthesis and detoxification of xenobiot-ics, and disturbance of these functions can be linked to cell injury (53). Prolonged exposure to ethanol induces proliferation of the ER of in the liver and enhanced activity of cytochrome P450 enzymes, which in turn can result in production of hepatotoxic or carcinogenic metabolites (54). 

When considering the mechanism by which drug causes nephrotoxicity, two components of renal function are decisive. The first are the renal transport processes which are critical to recovering essential minerals and nutrients from the glomerular filtrate and the second are the renal enzyme systems which are essential to both detoxification of xenobiotics and maintaining the bod)/ s acid/base homeostasis [22, 23]. 

In humans a microsomal form of EH (mEH) is also found. mEH can catalyze trans-hydration of epoxides and arene oxides yielding reactive diol-epoxides. Xenobiotic substrates include carcinogenic polycyclic aromatic hydrocarbons (PAHs). Whereas diol-epoxide products tend to be highly reactive and carcinogenic or mutagenic, mEH can catalyze the detoxification of xenobiotics as well. 

Renal tissue metabolism and transport mechanisms play important roles in the excretion and detoxification of xenobiotics (and/or their metabolites). Although the kidneys play an important part in the detoxification of xenobiotics, renal tissue may produce or increase the amounts of toxic metabolites received via the renal blood supply by metabolism (e.g., mixed-function oxidase reactions or concentrating effects within the nephron) (Piperno 1981 Commandeur and Vermeulen 1990 Goldstein 1994 Diamond and Zalups 1998 Endou 1998 Tarloff and Lash 2004). 

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