Xenobiotic bioactivation conjugation

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. 

Because bioactivation is mainly an activation of xenobiotics to electrophilic forms which are entities capable of reacting irreversibly with tissue nucleophiles, biotransformations leading to toxic metabolites are in most cases phase I reactions. However, phase II reactions may also give rise to toxic phenomena, e.g. when conjugation produces a toxic metabolite, or when it is responsible for a specific target organ toxicity by acting as delivery form to particular sites in the body where it is hydrolysed and exerts a localized effect. Also, the final toxic metabolite may be formed by combinations of several phase I and phase II reactions. 

Some examples of bioactivation to hepatotoxic or IDR electrophilic intermediates are shown in Fig. 10.33. Bioactivation may occur by both oxidation and conjugation reactions, such as those with diclofenac, which undergoes the formation of an acyl glucuronide and/or acyl CoA (acylator intermediates) or to produce iminoquinones via formation of a phenol intermediator (Fig. 10.33-1) (92). The anticonvulsant carbamazepine is 2-hydroxylated and the elimination of the amide group yields the reactive quinoneimine intermediate (Fig. 10.33-2), and the antidepressant paroxetine and other xenobiotics with the common methylenedioxyphenyl nucleus undergo methylene oxidation to a... 

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