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  • Aztreonam br Models of intrinsic DILI Animal models


    Models of intrinsic DILI Animal models of intrinsic DILI are straightforward with regard to technique. In most cases, one can simply treat the animals with a large dose of the drug of interest to cause hepatotoxicity. However, the proper use of these models requires a basic understanding of the mechanisms of toxicity in each one. The most common models of intrinsic hepatotoxicity are listed in Table 2. By far, the two most common models in intrinsic DILI research are acetaminophen (APAP) and carbon tetrachloride (CCl4).
    Models of idiosyncratic DILI The study of IDILI in animals poses greater technical challenges. Achieving an adverse reaction to a drug that is Aztreonam known to cause IDILI in humans typically requires a pre-treatment or genetic alteration designed to pre-dispose the animals to injury. Of course, any such pre-treatment has the potential to affect the clinical relevance of the model. The three major approaches that have been used so far involve either induction of inflammation, suppression of immune tolerance, or genetic manipulation of mitochondrial function. These models are summarized in Table 3.
    Suppression of immune tolerance (“Uetrecht-Pohl model”) A recently developed approach to model IDILI in animals is to suppress immune tolerance in the liver (Fig. 3). This approach is based on Temple's corollary, which states that all drugs that cause serious IDILI in a few patients also cause much higher incidences of mild liver injury that spontaneously resolves despite continued treatment. The fact that most patients adapt to the initial mild injury strongly suggests that immune tolerance develops and prevents progression to liver failure. That led to the hypothesis that breakage of immune tolerance is necessary to develop a complete IDILI model. Consistent with that, Metushi et al. [120] observed that the idiosyncratic hepatotoxicant amodiaquine causes delayed-onset mild liver injury in female C57Bl/6J mice that spontaneously resolves, and that resolution occurred after an increase in programmed cell death 1 protein (Pd-1) positive T Aztreonam in the liver. Importantly, Pd-1 is critical for development of immune tolerance. The authors later discovered that the injury appeared to be worse in Pd-1 KO (Pd-1−/−) mice [121], and that co-treatment of Pd-1−/− mice with an antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA4) on regulatory T cells prevented injury resolution [121]. At the same time, Chakraborty et al. [122] used a similar approach to delay resolution of halothane hepatotoxicity. Importantly, histology in both studies more closely resembled that of human IDILI than previous models [121,122]. Finally, a recent follow-up study demonstrated that the Pd-1−/−-anti-CTLA4 mouse model can also reproduce troglitazone and tolcapone IDILI, and can distinguish between hepatotoxic and non-hepatoxic drugs of the same class [14].
    Differences in drug metabolism between animals and humans Drug metabolism, and especially cytochrome P450-mediated metabolism, should be a major consideration when working with any model of DILI. It should be clear from our discussion of intrinsic DILI models that many depend upon metabolism to form a reactive metabolite. The prevailing view of IDILI is that it too depends upon reactive metabolites, which bind to proteins and create neoantigens that elicit an immune response (though other mechanisms have also been proposed) [116,130]. Importantly, there are dramatic species differences in metabolism. Although the common experimental models (mice, rats, dogs, and monkeys) all express homologs of the major P450s in humans, not all homologs have the same substrate specificity. In fact, CYP2E1 is the only human P450 that is functionally conserved across species [131]. Generally, mice bear the greatest resemblance in overall P450 function to humans among common research species, while rats are the most strikingly different [131]. Rats tend to have low P450 activity compared to other species, which may explain why they are less susceptible to some hepatotoxicants. Differences in expression or function of other enzymes can also be important. For example, dogs are poor acetylators because they lack N-acetyltransferase (Nat) genes [132] and the high incidence of idiosyncratic sulfonamide toxicity in dogs may be a result of that [133], while cats are poor glucuronidators and are highly susceptible to APAP hepatotoxicity because they lack functional Ugt1a6 [134]. Overall, it is critical to consider species differences in drug metabolism when using animal models of DILI.