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Testing Possible Risk Factors for Idiosyncratic Drug-Induced Liver Injury Using an Amodiaquine Mouse Model and Co-treatment with 1-Methyl-d-Tryptophan or Acetaminophen.

ABSTRACT: Idiosyncratic drug reactions are unpredictable adverse reactions. Although most such adverse reactions appear to be immune mediated, their exact mechanism(s) remain elusive. The idiosyncratic drug reaction most associated with serious consequences is idiosyncratic drug-induced liver injury (IDILI). We have developed a mouse model of amodiaquine (AQ)-induced liver injury that reflects the clinical characteristics of IDILI in humans. This was accomplished by impairing immune tolerance by using PD-1^-/- mice and an antibody against CTLA-4. PD-1 and CTLA-4 are known negative regulators of lymphocyte activation, which promote immune tolerance. Immune checkpoint inhibitors have become important tools for the treatment of cancer. However, as in our model, immune checkpoint inhibitors increase the risk of IDILI with drugs that have an incidence of causing liver injury. Agents such as 1-methyl-d-tryptophan (D-1-MT), an inhibitor of the immunosuppressive indoleamine 2,3-dioxygenase (IDO) enzyme, have also been proposed as anti-cancer treatments. Another possible risk factor for the induction of an immune response is the release of danger-associated molecular patterns (DAMPs). Acetaminophen (APAP) is known to cause acute liver injury, and it is likely to cause the release of DAMPs. Therefore, either of these agents could increase the risk of IDILI, although through different mechanisms. If true, then this would have clinical implications. We found that co-treatment with D-1-MT paradoxically decreased liver injury in our model, and although APAP appeared to slightly increase AQ-induced liver injury, the difference was not significant. Such results highlight the complexity of the immune response, which makes potential interactions difficult to predict.

SUBMITTER: Cho T

PROVIDER: S-EPMC7905801 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Acetaminophen (APAP) overdose leads to severe hepatotoxicity. Osthole, a natural coumarin found in traditional Chinese medicinal herbs, has therapeutic potential in the treatment of various diseases. In this study, we investigated the effects of osthole against APAP-induced hepatotoxicity in mice. Mice were administered osthole (100 mg·kg-1·d-1, ip) for 3 d, then on the fourth day APAP (300 mg/kg, ip) was co-administered with osthole. The mice were euthanized post-APAP, their serum and livers were collected for analysis. Pretreatment with osthole significantly attenuated APAP-induced hepatocyte necrosis and the increases in ALT and AST activities. Compared with the mice treated with APAP alone, osthole pretreatment significantly reduced serum MDA levels and hepatic H2O2 levels, and improved liver GSH levels and the GSSG-to-GSH ratio. Meanwhile, osthole pretreatment markedly alleviated the APAP-induced up-regulation of inflammatory cytokines in the livers, and inhibited the expression of hepatic cytochrome P450 enzymes, but it increased the expression of hepatic UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs). Furthermore, osthole pretreatment reversed APAP-induced reduction of hepatic cAMP levels, but pretreatment with H89, a potent selective PKA inhibitor, failed to abolish the beneficial effect of osthole, whereas pretreatment with L-buthionine sulfoximine, a GSH synthesis inhibitor, abrogated the protective effects of osthole on APAP-induced liver injury, and abolished osthole-caused alterations in APAP-metabolizing enzymes. In cultured murine primary hepatocytes and Raw264.7 cells, however, osthole (40 μmol/L) did not alleviate APAP-induced cell death, but it significantly suppressed APAP-caused elevation of inflammatory cytokines. Collectively, we have demonstrated that osthole exerts a preventive effect against APAP-induced hepatotoxicity by inhibiting the metabolic activation of APAP and enhancing its clearance through an antioxidation mechanism.

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Testing Possible Risk Factors for Idiosyncratic Drug-Induced Liver Injury Using an Amodiaquine Mouse Model and Co-treatment with 1-Methyl-d-Tryptophan or Acetaminophen.

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