Mechanism-Based Inactivation of Human Cytochromes P450s: Experimental Characterization, Reactive Intermediates, and Clinical Implications

摘要: The P450 type cytochromes are responsible for the metabolism of a wide variety xenobiotics and endogenous compounds. Although P450-catalyzed reactions generally thought to lead detoxication xenobiotics, can also produce reactive intermediates that react with cellular macromolecules leading toxicity or P450s form them irreversible (i.e., mechanism-based) inactivation. This perspective describes fundamentals mechanism-based inactivation as it pertains enzymes. experimental approaches used characterize inactivators discussed, criteria required compound be classified inactivator outlined. kinetic scheme calculation relevant constants describe particular event presented. structural aspects important functional groups several classes molecules have been found impart upon by such acetylenes, thiol-containing compounds include isothiocyanates, thiazolidinediones, thiophenes, arylamines, quinones, furanocoumarins, cyclic tertiary amines described. Emphasis throughout this is placed on more recent findings human where site modification, whether apoprotein heme moiety, and, at least in part, identity intermediate loss activity known inferred. Recent advances trapping procedures well new methods identification A clinically drugs act discussed. these has potential causing serious drug-drug interactions may severe toxicological effects. clinical significance inactivating improving drug efficacy safety discussed along exploiting therapeutic benefits.