The importance of hapten–protein complex formation in the development of drug allergy

Faulkner, Lee; Meng, Xiaoli; Park, B. Kevin; Naisbitt, Dean J.

doi:10.1097/aci.0000000000000078

Cited by 55 publications

(55 citation statements)

References 64 publications

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“…273 The β-lactam antibiotics, such as amoxicillin (AX), are among the most widely prescribed drugs and frequently elicit allergic reactions. 274,275 The covalent adduction of AX, other antibiotics, and drugs to proteins is considered a key process for the allergic response. 274,275 In the case of AX, covalent modification occurs through nucleophilic attack of the β-lactam ring and adduction by the ε-amino group of Lys in proteins (Figure 15).…”

Section: Adduct Formation With Therapeutic Drugsmentioning

confidence: 99%

“…274,275 The covalent adduction of AX, other antibiotics, and drugs to proteins is considered a key process for the allergic response. 274,275 In the case of AX, covalent modification occurs through nucleophilic attack of the β-lactam ring and adduction by the ε-amino group of Lys in proteins (Figure 15). This process gives rise to a haptenized penicilloyl–protein adduct, which can elicit an immune response.…”

Section: Adduct Formation With Therapeutic Drugsmentioning

confidence: 99%

See 1 more Smart Citation

Biomonitoring Human Albumin Adducts: The Past, the Present, and the Future

Sabbioni¹,

Turesky

2016

Chem. Res. Toxicol.

105

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Serum albumin (Alb) is the most abundant protein in blood plasma. Alb reacts with many carcinogens and/or their electrophilic metabolites. Studies conducted over 20 years ago showed that Alb forms adducts with the human carcinogens aflatoxin B1 and benzene, which were successfully used as biomarkers in molecular epidemiology studies designed to address the role of these chemicals in cancer risk. Alb forms adducts with many therapeutic drugs or their reactive metabolites such as β-lactam antibiotics, acetylsalicylic acid, acetaminophen, nonsteroidal anti-inflammatory drugs, chemotherapeutic agents, and antiretroviral therapy drugs. The identification and characterization of the adduct structures formed with Alb have served to understand the generation of reactive metabolites and to predict idiosyncratic drug reactions and toxicities. The reaction of candidate drugs with Alb is now exploited as part of the battery of screening tools to assess the potential toxicities of drugs. The use of gas chromatography-mass spectrometry, liquid chromatography, or liquid chromatography-mass spectrometry (LC-MS) enabled the identification and quantification of multiple types of Alb xenobiotic adducts in animals and humans during the past three decades. In this perspective, we highlight the history of Alb as a target protein for adduction to environmental and dietary genotoxicants, pesticides, and herbicides, common classes of medicinal drugs, and endogenous electrophiles, and the emerging analytical mass spectrometry technologies to identify Alb-toxicant adducts in humans.

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Section: Adduct Formation With Therapeutic Drugsmentioning

confidence: 99%

Section: Adduct Formation With Therapeutic Drugsmentioning

confidence: 99%

Biomonitoring Human Albumin Adducts: The Past, the Present, and the Future

Sabbioni¹,

Turesky

2016

Chem. Res. Toxicol.

105

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show abstract

“…Drugs can bind HLA in at least 3 possible ways. First, drugs may act as haptens forming covalent interactions with peptides that bind HLA molecules associated with ADRs (e.g., penicilloyl-modified peptides) (36). Second, drugs may bind directly to the TCR or HLA molecules outside of the antigen-binding cleft with rapid non-covalent interactions (called the pharmacological interactions with immune receptors [pi] hypothesis) (37).…”

Section: Similarity: Hla Associationsmentioning

confidence: 99%

New approaches for predicting T cell–mediated drug reactions: A role for inducible and potentially preventable autoimmunity

Michels

Ostrov

2015

Journal of Allergy and Clinical Immunology

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Adverse drug reactions (ADRs) are commonplace and occur when a drug binds to its intended pharmacological target (Type A ADR) or an unintended target (Type B ADR). Immunologically mediated Type B ADRs, such as drug hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), can be severe and result in a diverse set of clinical manifestations that include fever and rash as well as multiple organ failure (liver, kidney, lungs, and/or heart) in the case of drug hypersensitivity syndrome. There is increasing evidence that specific HLA alleles influence the risk of drug reactions. Several features of T cell–mediated ADRs are strikingly similar to those displayed by autoimmune diseases like type I diabetes, such as strong HLA association, organ-specific adaptive immune responses, viral involvement, and activation of innate immunity. There is a need to better predict patient populations at risk for developing immunologically mediated Type B ADRs. Since methods to predict type 1 diabetes using genetic and immunological biomarkers have been developed to a high level of accuracy (predicting 100% of individuals likely to progress), new research strategies based on these methods may also improve the ability to predict drug hypersensitivity.

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“…With non-beta-lactum drugs the formation of haptenprotein complexes usually does not take place unless generation of reactive intermediates with proteins occurs. This process has been described with several drugs , such as sulphonamides, nevirapine and carbamazepine, in the review by Faulkner et al [14]. One of the major problems in protein haptenation is following the hapten after binding to the endogenous proteins.…”

mentioning

confidence: 96%

“…The role of hapten-protein formation and the development of drug allergy have been reviewed by Faulkner et al [14], in which they have analysed the formation of hapten-protein complexes, and assessed the relevance of this in the immunological response to drugs. Drugs by themselves or their metabolites bind to endogenous proteins and can generate an immune response.…”

mentioning

confidence: 99%