Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5849_Библиотеки_им_академика_М_И_Перельмана

1000 patients experiences transient elevations of liver enzymes in serum (including ALT, ALP, etc.), and only 1 in 1000 to 1 in 10,000 patients goes on to develop irreversible liver injury. The term “idiosyncratic liver injury” is often used to describe this rare incidence of hepatotoxicity. Such patient idiosyncrasy, on top of the lack of good predictivity of animal models mentioned earlier [4], has made it even more challenging to identify the exact mechanism(s) of DILI in a particular patient and drug situation. It is well-known that the normal human liver has an incredible ability to adapt to injury. However, in susceptible patients with particular circumstances (such as underlying disease and conditions), continuous toxicant insult could eventually lead to “full-blown” liver injury. There is now general recognition that several potential mechanisms of DILI are frequently associated with hepatotoxic drugs, sometimes with multiple mechanisms within the same patient and drug situatio n. These mechanisms include repeated and excessive generation of reactive metabolites that cannot be cleared, mitochondrial inhibition and/or dysfunction that cannot be regenerated, generation of excessive oxidative stress leading to oxidative damage that cannot be sufficiently repaired, and disruption of bile acid homeostasis that cannot be counterbalanced [8]. Notice the deliberate mention of both concepts of “damage” and “repair” in each mechanism. While “damage” may be initiated by a drug, lack of sufficient “repair” may be largely determined by a patient’s host factors. The job of medicinal chemists is to find drugs that are less likely to cause damage (i.e., first do no harm). Better understanding of these drug “damage” mechanisms have led to the development of experimental models and assay systems suitable for both character­izing such toxic mechanisms, and selecting better drug candidates in the earlier phases of drug discovery and development.

is susceptible to bioactivation; (ii) is there an alternative (higher affinity but innocuous) route of metabolism within the molecule that minimizes the potential bioactivation of the toxicophore; and (iii) are there parallel competing detoxification pathways that can scavenge the reactive metabolite or its precursor [19]. Furthermore, whether tissue injury will occur as a result of bioactivation depends on additional host factors such as toleration to injury and adaptability to tissue repair. Hence, it is exceptionally challenging (if not impossible) to establish a direct correlation between bioactivation findings in vitro and toxicity outcomes in vivo.

Mitochondria generate 95% of the cell’s energy. This occurs in the electron transport chain, which contains four oxidative phosphorylation (OXPHOS) com­plexes (or complex I–IV) and an ATPase (or complex V). Oxidizable substrates from glycolysis, fatty acid, or protein catabolism enter the mitochondrion in the form of acetyl-CoA, or as other intermediaries of the Krebs cycle. Reducing equivalents in the form of NADH and FADH pass electrons to complex I (NADH-ubiquinone oxido­reductase), or complex II (succinate dehydrogenase) of the electron transport chain, respectively. Electrons pass from complex I and II to complex III (ubiquinol­cytochrome c oxidoreductase) and then to complex IV (cytochrome c oxidase), accumulating four elect rons in the process. The four electrons then tetravalently reduce O