Scope of Drug Metabolism toward Xenobiotic Detoxification

Over the course of evolution organisms were exposed to environmental compounds of negligible nutritive value. These have variably been called 'foreign compounds' or 'xenobiotics.' Also the term 'drug' is used for them in contrast to the narrower term 'therapeutic drug' to specifically designate those xenobiotics that are intended for clinical use. Organisms that developed systems enabling them to get rid of these xenobiotics before they could accumulate to toxic levels had an evolutionary advantage. Such systems therefore had an obvious scope toward detoxification.1

The major excretory systems of mammals - the renal and the biliary excretion system - require a minimal hydrophilicity of chemical compounds to be excretable. This generated the necessity for lipophilic xenobiotics to be converted to hydrophilic metabolites in order to become excretable.1-3 This necessity represented one driving force for the metabolism of xenobiotics to develop during evolution.

A further need was the ability to detoxify 'future unknowns.' Therefore, the enzymes exclusively or predominantly catalyzing the metabolism of xenobiotics usually: (1) have a very broad substrate specificity; and (2) exist in large families or superfamilies of enzymes each one of them possessing a broad but distinct substrate specificity, which in part overlaps with the specificities of the other isoenzymes.1 The catalytically active site of a typical drug-metabolizing enzyme must be able to accommodate a large number of substrates such that the fit of an individual substrate to the active site cannot be very tight. An important consequence of this is that the geometry of the substrate/catalytic site is not optimized for maximal speed of the reaction but rather for substantial flexibility. Therefore, drug-metabolizing enzymes are relatively slow enzymes.1 Glutathione S-transferases are among the fastest of them (approximately 104 mole substrate turned over per minute per mole of enzyme). Even this is very slow compared with fast enzymes such as carboanhydrase (turnover number about 4 x 107 min— 1).

Natural Detox

Natural Detox

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