Immunochemical detection of flucloxacillin adduct formation in livers of treated rats

Carey, Michelle A.; Pelt, Frank N.A.M. van

doi:10.1016/j.tox.2005.07.015

Cited by 44 publications

(36 citation statements)

References 23 publications

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“…Studies have similarly detected flucloxacillin bound to both tissue and serum proteins in vivo using adduct-specific antibodies [61]. Advanced mass spectrometry techniques used to characterize the modification sites following flucloxacillinhuman serum albumin conjugation associated with the stimulation of a drug-specific T-cell response revealed modification at lysine residues in 8/8 flucloxacillin-tolerant patients with Lys190 and Lys212 modified in 8/8 patients [62].…”

Section: Hapten/prohapten Hypothesismentioning

confidence: 99%

Human leukocyte antigen genetic risk factors of drug-induced liver toxicology

Grove

Aithal

2014

Expert Opinion on Drug Metabolism & Toxicology

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Increasing evidence points to a crucial role for the adaptive immune system in the pathogenesis of DILI. Identification of specific HLA alleles as risk factors through large genome-wide association studies has been instrumental in this and in vitro analyses have facilitated improved understanding of the molecular mechanisms. This provides the basis for developing clinical pharmacogenomic applications. Already, genotyping for hypersensitivity HLA risk alleles has been implemented and opportunities for pre-prescription testing in DILI identified. However, although associations are strong, the rarity of DILI means routine testing has not been formally evaluated. Nevertheless, enhanced understanding of how HLA alleles contribute to injury risk is valuable for drug development. Translation of this research into effective pre-emption and primary prevention remains the goal.

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Section: Hapten/prohapten Hypothesismentioning

confidence: 99%

Human leukocyte antigen genetic risk factors of drug-induced liver toxicology

Grove

Aithal

2014

Expert Opinion on Drug Metabolism & Toxicology

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“…In addition, a different anti-amoxicillin antibody has been employed in immunohistochemistry studies showing the distribution of the antibiotic in various tissues in rats [80] and its correlation with the presence of penicillin transporters at these sites. An antibody against a rabbit serum albuminflucloxacillin conjugate has also been developed that recognizes flucloxacillin-adducted proteins in liver extracts from flucloxacillin-treated rats [81]. Moreover, there are commercial antibodies against penicillin that can recognize amoxicillin-protein adducts, although with lower sensitivity than benzyl-penicillin adducts [62].…”

Section: Proteomics In the Elucidation Of The Mechanisms Involved In mentioning

confidence: 99%

Adduct Formation and Context Factors in Drug Hypersensitivity: Insight from Proteomic Studies

González-Morena¹,

Montanez²,

Aldini³

et al. 2017

CPD

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Drug hypersensitivity reactions result from the activation of the immune system by drugs or their metabolites. The clinical presentations of drug hypersensitivity can range from relatively mild local manifestations to severe systemic syndromes that can be life-threatening. As in other allergic reactions, the causes are multifactorial as genetic, metabolic and concomitant factors may influence the occurrence of drug hypersensitivity. Formation of drug protein adducts is considered a key step in drug adverse reactions, and in particular in the immunological recognition in drug hypersensitivity reactions. Nevertheless, non-covalent interactions of drugs with receptors in immune cells or with MHC clefts and/or exposed peptides can also play an important role. In recent years, development of proteomic approaches has allowed the identification and characterization of the protein targets for modification by drugs in vivo and in vitro, the nature of peptides exposed on MHC molecules, the changes in protein levels induced by drug treatment, and the concomitant modifications induced by danger signals, thus providing insight into context factors. Nevertheless, given the complexity and multifactorial nature of drug hypersensitivity reactions, understanding the underlying mechanisms also requires the integration of knowledge from genomic, metabolomic and clinical studies.

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“…Yet, patients with homozygous expression of C-25385T have lower expression of PXR and decreased induction of CYP3A4 expression, suggesting that higher levels of the parental compound are present in liver. Because flucloxacillin can form adducts that elicit an immune response to induce the apoptosis of hepatic cells [48], the reduced amount of PXR in those with the C-25385T substitution could lead to hepatocellular injury. These studies also indicate that PXR may have a dichotomous role in flucloxacillin-induced hepatotoxicity.…”

Section: Pxr-mediated Hepatotoxicity and Its Underlying Mechanismsmentioning

confidence: 99%

Pregnane X receptor and drug-induced liver injury

Wang

Chai

Brewer

et al. 2014

Expert Opinion on Drug Metabolism & Toxicology

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Introduction The liver plays a central role in transforming and clearing foreign substances. The continuous exposure of the liver to xenobiotics sometimes leads to impaired liver function, referred to as drug-induced liver injury (DILI). The pregnane X receptor (PXR) tightly regulates the expression of genes in the hepatic drug-clearance system and its undesired activation plays a role in DILI. Areas covered This review focuses on the recent progress in understanding PXR-mediated DILI and highlights the efforts made to assess and manage PXR-mediated DILI during drug development. Expert opinion Future efforts are needed to further elucidate the mechanisms of PXR-mediated liver injury, including the epigenetic regulation and polymorphisms of PXR. Novel in vitro models containing functional PXR could improve our ability to predict and assess DILI during drug development. PXR inhibitors may provide chemical tools to validate the potential of PXR as a therapetic target and to develop drugs to be used in the clinic to manage PXR-mediated DILI.

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Immunochemical detection of flucloxacillin adduct formation in livers of treated rats

Cited by 44 publications

References 23 publications

Human leukocyte antigen genetic risk factors of drug-induced liver toxicology

Human leukocyte antigen genetic risk factors of drug-induced liver toxicology

Adduct Formation and Context Factors in Drug Hypersensitivity: Insight from Proteomic Studies

Pregnane X receptor and drug-induced liver injury

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