Conjugates xenobiotic lipid

The majority of xenobiotics that enter the body tissues are lipophilic, a property that enables them to penetrate lipid membranes and to be transported by lipoproteins in body fluids. The metabolism of xenobiotics, carried out by a number of relatively nonspecific enzymes, usually consists of two phases. During phase I, a polar group is introduced into the molecule and although this increases the molecule s water solubility, the most important effect is to render the xenobiotic a suitable substrate for phase II reactions. In phase II reactions, the altered compounds combine with an endogenous substrate to produce a water-soluble conjugation product that is readily excreted. Although this sequence of events is generally a detoxication mechanism, in some cases the intermediates or final products are more toxic than the parent compound, and the sequence is termed an activation or intoxication mechanism. See Chapter 20 for discussion of activation and toxicity. 

Some metabolic conjugative processes result in the production of lipophilic derivatives that are not readily eliminated. While their physical properties are different from the classical hydrophilic conjugates, the mechanism of formation clearly defines them as conjugates (i.e., they are formed as the result of a union of xenobiotic metabolites with endogenous molecules). The reactions involve the coupling of xenobiotic acids and alcohols with endogenous intermediates of lipid synthesis (i. e., the acids with glycerol and cholesterol and the alcohols with the fatty acids). 

With lipophilic conjugation, the xenobiotic metabolites appear to be incorporated in the lipid biosynthetic pathway similar to the normal constituents. One would expect the conjugates to have turnover times similar to that of their natural counterparts. Whether the lipophilic conjugates have any deleterious effect on the organism would depend upon the type and amount of bioactivity retained by the metabolites before and after conjugation. 

Conjugation of lipophilic xenobiotics to polar cellular constituents renders the xenobiotic more water-soluble. While the lipophilic parent xenobiotics could readily diffuse into the cells, the increase in polarity associated with conjugation greatly reduces the ability of the compound to diffuse across the lipid bilayer of the cell membrane thus trapping the compound within the cell. The polar conjugates must therefore rely upon active transport processes to facilitate efflux from the cell. Hepatocytes, as well as other cells involved in chemical detoxification, are rich with members of the ATP-binding cassette superfamily of active transport proteins (ABC transporters). Cellular efflux of xenobiotics by these transporters is often referred to as Phase III elimination because Phase I or II detoxification processes often precede and are a requirement of Phase III elimination. A detailed description and discussion of elimination and transporters is presented in Chapter 15. 

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. 

Rich in both phase I (principally the cytochromes P450, catalyzing hydrolysis, reduction, and oxidation reactions) and phase II (catalyzing conjugation of xenobiotic molecules with hydrophilic moieties) biotransforming enzymes, the liver is the metabolic center of the body. In fact, most of the field of biochemistry is concerned with its metabolic reactions. The liver essentially converts ingested food into a balanced cell culture medium via metabolic interconversion of amino acids, carbohydrates, and lipids and synthesizes many substances that are subsequently exported for use in other areas of... 

Not all xenobiotic metabolites are readily eliminated from the body. Some of the conjugates produced in Phase II metabolism have lipophilic character and are included in the biosynthesis of body lipids. These can be retained in the body and have delayed toxic effects. 

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 ). 

This class of lipid conjugates Is the most nonpolar yet Identified, a characteristic which Is often useful In pursuing the Identification of unknown metabolites. The first cholesterol ester of a xenobiotic was reported In 1976 for a saturated methoprene metabolite which contributed 15% of the total C-resldue In the liver of a chicken given a single oral dose of methoprene at 64 mg/kg (17). The tai-cyc lop ropy 1 fatty acids derived from cycloprate also form esters of cholesterol. Three such esters contributed 5% of the total residual radiocarbon In rat carcasses four days after a single oral dose of cycloprate at 21 mg/kg ( ). 

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