Lipophilic conjugates discussion

This presentation will not be a review, but will attempt to place within a frame of the presently used techniques and methods my very personal experiences and views. This discussion will be limited to the "classical" pqlar conjugates. Very different methodology is required to purify the non polar "lipophilic" conjugates. Furthermore, only methods that result in the Isolation of intact conjugates in amounts adequate for multiple-method structural Identification studies will be discussed (i.e. combined methods such as GC-MS and HPLC-MS and derivatization techniques will not be covered). 

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. 

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. 

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