Immunogenicity of Amodiaquine in the Rat

Clarke, Jessica L.; Maggs, J L; Kitteringham, NR; Park, B.K.

doi:10.1159/000235138

Cited by 62 publications

(43 citation statements)

References 25 publications

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“…Histopathology shows necrosis and the presence of inflammatory cells including Kupffer cells (Larrey et al, 1986;Neftel et al, 1986). It has also been reported that there are circulating anti-AQ IgG antibodies in humans who developed a severe adverse reaction (Clarke et al, 1991), and anti-AQ antibodies were also observed in rats (Clarke et al, 1990). These observations suggest that the mechanism of AQ-induced IDILI is an immune-mediated reaction.…”

Section: Introductionmentioning

confidence: 94%

Development of a novel mouse model of amodiaquine-induced liver injury with a delayed onset

Metushi¹,

Cai

Dervovic

et al. 2014

Journal of Immunotoxicology

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Amodiaquine (AQ) treatment is associated with a high incidence of idiosyncratic drug-induced liver injury (IDILI) and agranulocytosis. Evidence suggests that AQ-induced IDILI is immune mediated. A significant impediment to mechanistic studies of IDILI is the lack of valid animal models. This study reports the first animal model of IDILI with characteristics similar to mild IDILI in humans. Treatment of female C57BL/6 mice with AQ led to liver injury with delayed onset, which resolved despite continued treatment. Covalent binding of AQ was detected in the liver, which was greater in female than in male mice, and higher in the liver than in other organs. Covalent binding in the liver was maximal by Day 3, which did not explain the delayed onset of alanine aminotransferase (ALT) elevation. However, coincident with the elevated serum ALT, infiltration of liver and splenic mononuclear cells and activation of CD8 T-cells within the liver were identified. By Week 7, when ALT levels had returned close to normal, down-regulation of several inflammatory cytokines and up-regulation of PD-1 on T-cells suggested induction of immune tolerance. Treatment of Rag1 À/À mice with AQ resulted in higher ALT activities than C57BL/6 mice, which suggested that the adaptive immune response was responsible for immune tolerance. In contrast, depletion of NK cells significantly attenuated the increase in ALT, which implied a role for NK cells in mild AQ-induced IDILI. This is the first example of a delayed-onset animal model of IDILI that appears to be immune-mediated.

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Section: Introductionmentioning

confidence: 94%

Development of a novel mouse model of amodiaquine-induced liver injury with a delayed onset

Metushi¹,

Cai

Dervovic

et al. 2014

Journal of Immunotoxicology

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“…Nevertheless, their role in the pathogenesis of agranulocytosis remains to be established. Further studies should consider the possible relationships between cellular susceptibility and immune responsiveness to AQ and its metabolites since AQ has been shown to be immunogenic in man and experimental animals (Christie et al, 1989;Clarke et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

The toxicity of amodiaquine and its principal metabolites towards mononuclear leucocytes and granulocyte/monocyte colony forming units.

Winstanley

Coleman

Maggs

et al. 1990

Brit J Clinical Pharma

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The cytotoxicity of amodiaquine (AQ), amodiaquine quinoneimine (AQQI) and desethylamodiaquine (AQm) has been assessed in comparison with that of chloroquine (CQ) using mononuclear leucocytes (MNL) and granulocyte/monocyte colony forming units (GM‐CFU) from haematologically normal subjects. Toxicity toward MNL was assessed after 2 h and 16 h incubations with each compound. After 2 h, AQ, AQm and AQQI but not CQ (within the concentration range 1‐100 mumols l‐1) produced a significant decrease in cell viability. After 16 h, all four compounds significantly increased cell death. After both 2 h and 16 h incubations CQ was the least toxic and AQQI the most toxic of the four compounds towards MNL. Toxicity to GM‐CFU was assessed by the inhibition of colony formation in vitro. After 10‐14 days incubation, there was significant concentration‐dependent inhibition of colony formation by AQ, AQm, AQQI and CQ (within the range 0.1‐10.0 mumols l‐ 1). There were no significant differences between the ability of the four compounds to inhibit colony formation but toxicity towards GM‐CFU was observed at drug concentrations at least 10‐fold lower than those that were toxic to MNL. These data show that the four compounds are equally toxic in vitro toward GM‐CFU, although some differences in their toxicity toward MNL were seen. The possible mechanisms of AQ's toxicity are discussed.

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“…22 People with mutant genotypes of CYP2C8, CYP1A1 and CYP1B1 have been found to have immunogenic adverse reactions to amodiaquine. [23][24][25][26][27][28] Wide variations in the CYP2C8 genotype mean that individuals experience broad differences in the drug's efficacy and toxicity. Evidence suggests that decreased function of the CYP2C8 enzyme impairs metabolism of the drug and can form a toxic metabolite that causes hepatotoxicity and agranulocytosis.…”

Section: The Case Of Amodiaquinementioning

confidence: 99%