CYP Inhibition and Autoimmune Diseases

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). 

There are several examples of autoimmune hepatitis caused by mechanism-based inhibitors in the field of CYPs hepatitis induced by halothane (CYP2E1) [15,16], by tienilic acid (CYP2C9) [17] and by dihydralazine (CYP1A2) [18,19]. 

In the case of tienilic acid induced hepatitis, Beaune et al. [20] have shown that autoantibodies against CYP2C9 are present in the serum of patients suffering from the disease. Additional in vitro evidence has shown the potential for tienilic acid to alkylate CYP2C9 [21]. 

An autoimmune response is rarely detected during preclinical drug development because of the lack of good predictive animal models for the human immune system. Owing to their low incidence and idiosyncratic nature, autoimmune diseases quite often appear as a serious issue only after product launch [2,22]. 

Structural Features Often Responsible for Mechanism-Based CYP Inhibition 

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