Metabolic activation, organic reactive intermediates

Toxic reactions occur by several mechanisms activation of metabolism, production of reactive intermediates and subsequent reactions with cell macromolecules, changing receptor responses, or through abnormal defence reactions. Several compounds cause toxicity by mimicking the organism s own hormones or neurotransmitters, or activating the body s endogenous receptors in some non-physiological way. ... 

Thus, the susceptibility is the result of accumulation of the drug in the target organ to reach concentrations not achieved in other tissues. This is then followed by what is probably a combination of events such as formation of a reactive intermediate, possibly a free radical, stimulation of lipid peroxidation and depletion of GSH, and then peroxidative damage to cell membranes and mitochondria. Whether metabolic activation by cytochromes P-450, or chemical rearrangement, or reductive activation, or all the three are involved is not currently clear. 

Some components of the immune system have metabolic capability including some forms of the cytochrome P450 system. Therefore, some chemicals, which are inert in their parent form but can be metabolized to reactive intermediates, can be activated by the immune system. However, it is important to emphasize that the metabolic capability of the immune system is minor when compared with other organ systems, most notably the liver, and that it possesses only a small repertoire of metabolizing enzymes. This point is discussed below as a major type of indirect mechanism of immunosuppression. 

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