Electrophilic metabolites, activation

A rare but serious event that can result from irreversible CYP inhibition is the development of a hypersensitivity reaction. The bioactivation of a drug and the formation of a covalent adduct between the activated substrate and the enzyme can lead to hapten formation and eventually to an idiosyncratic autoimmune response (usually in the form of autoimmune hepatitis) [14]. The hapten formation is the first key step toward the autoimmune response. The CYP macromolecule is made immunogenic ( foreign ) by the covalent binding of the electrophilic metabolites, and the immune reaction follows with the production of autoantibodies against the target molecule (not necessarily alkylated). 

For compounds that require metabolic activation, resonance stabilization of the electrophilic metabolites is important. This is because resonance stabilization... 

For compounds that require metabolic activation, avoiding structural features that may provide resonance stabilization of electrophilic metabolites (e.g., conjugated double bonds, or conjugated system/aryl moiety) will decrease the lifetime of the reactive intermediates. 

If chemical carcinogens or their electrophilic metabolites induce genetic changes which directly or in association with other cellular dysfunctions result in the malignant transformation of normal cells to potential tumor cells, then by the detection of mutagenic activity potential carcinogens could be identified. 

A frequent mechanism of DILI is the metabolic activation of drugs by cytochrome P450 (CYP) into chemically reactive, electrophilic metabolites, which react with and covalently bind to hepatic proteins and glutathione (Pessayre 1995). These reactive metabolites can trigger hepatitis through direct toxicity or immune reactions (Robin et al. 1997 Pessayre et al. 1999). 

The precise mechanism of chemical carcinogenesis is not known, but it is thought that in some instances it involves the formation of chemical adducts in the genetic material through covalent binding of nucleophilic sites by electrophilic parent compounds or their activated electrophilic metabolites (Cheever et al. 1991). Therefore, it seems that the capacity of MBOCA to form adducts with tissue DNA (Cheever et al. 1990), hemoglobin (Cheever et al. 1991 Sabbioni and Neumann... 

Metabolic activation has been incorporated into most shortterm j n vjjfro assays, usually by use of a mammalian liver microsomal preparation. Some genotoxicants have to be converted into reactive forms before producing observable effects. Metabolism by oxidative enzymes and formation of electrophilic metabolites that bind covalently to deoxyribonucleic acid (DNA) ( I2,23)... 

If activation of procarcinogens to electrophilic metabolites is enhanced, the expectable result is an increase in the number of carcinogenically active molecules capable of initiating cancer. Conversely, as deactivation or detoxification increases, one would expect lesser amounts of potentially carcinogenic metabolites available to initiate cancer induction. 

It s apparent that CYPs are involved in the metabolism of all but one, Plavix (clopido-grel), and even for that compound they re important downstream, after initial hydrolysis of the ester. What s not apparent from the figure is that metabolism isn t always something that limits drug effectiveness. Some drugs like valsartan are mostly excreted unchanged, while for others, like the top-seller Lipitor (atorvastatin) metabolism affords compounds that are still active. In Lipitor s case, active metabolites are said to account for 70% of the pharmacodynamic (PD) effect the drug produces. Much more worrisome would be reactive (electrophilic) metabolites that make for toxicity or metabolites that affect GYP expression or function. 

Sulfation of hydroxylamines and hydroxyamides often leads to reactive electrophilic metabolites (Abu-Zeid et al., 1992 Banoglu, 2000), but in the case of the prodrug minoxidil, sulfation of the N-oxide yields the active drug (Anderson et al., 1998) ... 

---