Reactive intermediate-mediated bioactivation

In the case of reactive intermediate-mediated teratogenesis, the reactive intermediates and ROS are typically too unstable to be formed maternally and cross the placenta. Accordingly, maternal pathways do not contribute directly to this mechanism, whereas the activities of embryonic and fetal enzymes catalyzing xenobiotic bioactivation and the detoxification of xenobiotic reactive intermediates and ROS play a key role in determining the adverse developmental consequences of xenobiotic exposure (see Sect.3 on Reactive intermediate-mediated mechanisms). 

Where drug are shown to form reactive intermediates by specific enzyme systems, it might be expected that the polymorphism or absence of these systems would track idiosyncratic reactions but to date no such link has been established. In fact, the most confounding element of idiosyncratic reactions is their unpredictable nature and whilst reactive intermediates may present a risk factor the true nature of the response is likely to be multifactorial. Changes in dmg metabolizing capacity, affecting the balance of bioactivation and bioinactivation processes which may be mediated through concomitant infection may also be a contributory factor. 

In addition to oxygen free radicals, other compounds such a clozapine, olanzapine and procainamide induce reactive intermediates [8, 9]. Clozapine and olanzapine bioactivation is thought to occur through a nitrenium ion [20] however clozapine but not olanzapine induce toxicity to neutrophils. This can lead to an immune-mediated depletion of neutrophils and their precursors (CFU-GM) [21]. Also, nonsteroidal antiinflammatory drugs (NSAIDs) have pro-oxidant radicals that when metabolized could cause oxidative stress [22]. 

NATs are also involved in bioactivation reactions via O-acetylation of Y-hydroxylamines formed from CYP-mediated N-hydroxylation of arylamines. These bioactivation reactions form unstable acetoxy esters that decompose to highly reactive species, which bind to cellular DNA [83], The O-sulfonation of compounds catalyzed by SULTs can also result in the formation reactive intermediates. Recently, it has been shown that a-hydroxytamoxifen (derived from CYP-mediated hydroxy-lation of tamoxifen) is bioactivated by SULTs [177],... 

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