"Anti-liver/kidney microsome" (anti-LKM) autoantibodies have been found in the serum of patients with cryptogenic chronic hepatitis and with immunoallergic drug-induced hepatitis, such as those induced by halothane or by tienilic acid (called anti-LKM2 in this case). So far the nature of the human microsomal macromolecules recognized by these antibodies has not been determined. Here we show, by using immunoblot techniques, that among the macromolecules present in human adult liver microsomes, one protein called cytochrome P-450-8 is specifically recognized by most sera of patients containing anti-LKM2 antibodies but not by control serum. Human fetal liver microsomes that do not contain cytochrome P-450-8 are not recognized by the anti-LKM2 antibodies. It is also shown that anti-cytochrome P-450-8 antibodies as well as human serum containing anti-LKM2 antibodies specifically inhibit the hydroxylation of tienilic acid by human liver microsomes. These results indicate that anti-LKM2 antibodies appearing in patients with hepatitis and concomitant administration of tienilic acid are directed against a cytochrome P-450 isoenzyme that catalyzes the metabolic oxidation of this drug. This suggests a possible mechanism for the appearance of anti-organelle antibodies in a drug-induced hepatitis.

The inhibition of human cytochrome P450s (CYPs) is one of the most common mechanisms which can lead to drug-drug interactions. The inhibition of CYPs can be reversible (competitive or non-competitive) or irreversible. Irreversible inhibition usually derives from activation of a drug by CYPs into a reactive metabolite, which tightly binds to the enzyme active site, leading to a long lasting inactivation. This process is called "mechanism based inhibition" or "suicide inhibition". The irreversible inactivation usually implies the formation of a covalent bond between the metabolite and the enzyme, which can lead to hapten formation and can in some cases trigger an autoimmune-response. For these reasons it is of utmost importance to study the mechanism of the CYP inhibition of new potential drugs as early as possible during the drug discovery process. The literature on CYPs is vast and covers numerous aspects of their biology and biochemistry, however to our knowledge there is no general and systematic review focusing on mechanism-based inhibitors; we have reviewed the literature and compiled all the available data on chemical entities, which are known to be CYP suicide inhibitors. Each compound is reported together with its chemical structure, the CYP isoform and the parameters describing the inactivation. Literature references are reported together with their PMID (PubMed ID number) to allow a fast retrieval of the papers. This review offers a quick reference to help predict liabilities of new chemical entities without carrying out extensive in vitro work, and will hopefully help in designing safer drugs.