Identification and quantification of drug–albumin adducts in serum samples from a drug exposure study in mice

Switzar, Linda; Kwast, Lydia M.; Lingeman, H.; Giera, Martin; Pieters, Raymond; Niessen, W.M.A.

doi:10.1016/j.jchromb.2012.12.033

Cited by 15 publications

(13 citation statements)

References 36 publications

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“…However, we cannot rule out the possibility that NAPQI formed in hepatocytes diffuses out of the cells and binds to plasma proteins in situ . The latter would be consistent with the earlier finding in mice of APAP-hemoglobin adducts in red blood cells, which do not express cytochrome P450 enzymes (Axworthy et al, 1988) and the identification of adducts on serum albumin (Switzar et al, 2013). It is likely that both mechanisms are involved.…”

Section: Discussionsupporting

confidence: 92%

Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: Dose–response, mechanisms, and clinical implications

McGill

Lebofsky

Norris

et al. 2013

Toxicology and Applied Pharmacology

214

189

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At therapeutic doses, acetaminophen (APAP) is a safe and effective analgesic. However, overdose of APAP is the principal cause of acute liver failure in the West. Binding of the reactive metabolite of APAP (NAPQI) to proteins is thought to be the initiating event in the mechanism of hepatotoxicity. Early work suggested that APAP-protein binding could not occur without glutathione (GSH) depletion, and likely only at toxic doses. Moreover, it was found that protein-derived APAP-cysteine could only be detected in serum after the onset of liver injury. On this basis, it was recently proposed that serum APAP-cysteine could be used as diagnostic marker of APAP overdose. However, comprehensive dose-response and time course studies have not yet been done. Furthermore, the effects of co-morbidities on this parameter have not been investigated. We treated groups of mice with APAP at multiple doses and measured liver GSH and both liver and plasma APAP-protein adducts at various timepoints. Our results show that protein binding can occur without much loss of GSH. Importantly, the data confirm earlier work that showed that protein-derived APAP-cysteine can appear in plasma without liver injury. Experiments performed in vitro suggest that this may involve multiple mechanisms, including secretion of adducted proteins and diffusion of NAPQI directly into plasma. Induction of liver necrosis through ischemia-reperfusion significantly increased the plasma concentration of protein-derived APAP-cysteine after a subtoxic dose of APAP. While our data generally support the measurement of serum APAP-protein adducts in the clinic, caution is suggested in the interpretation of this parameter.

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Section: Discussionsupporting

confidence: 92%

Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: Dose–response, mechanisms, and clinical implications

McGill

Lebofsky

Norris

et al. 2013

Toxicology and Applied Pharmacology

214

189

View full text Add to dashboard Cite

show abstract

“…Clearly none of the drugs caused a clear change in any of the T-cell subsets, which may be linked to the low damaging insult of the drugs at the dosing regimens, as used in this study. Previous studies showed that exposure to APAP resulted in formation of NAPQI-albumin adducts in serum (Switzar et al 2013). Nevertheless, this did not result in effects on T-cell subsets, possibly also suggesting that the time-course of this experiment might just be too short to elicit clear adaptive immune responses.…”

Section: Discussionmentioning

confidence: 68%

“…formation of drug-protein adducts has been described for APAP (Switzar et al 2013). The widely-used nonsteroidal anti-inflammatory drug (NSAID) DF can induce rare but severe hepatotoxicity and also forms metabolites and subsequent drug-protein adducts (Boelsterli 2003;Naisbitt et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Oral exposure to immunostimulating drugs results in early changes in innate immune parameters in the spleen

Kwast

Fiechter

Kruijssen

et al. 2016

Journal of Immunotoxicology

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The development of immune-dependent drug hypersensitivity reactions (IDHR) is likely to involve activation of the innate immune system to stimulate neo-antigen specific T-cells. Previously it has been shown that, upon oral exposure to several drugs with immune-adjuvant capacity, mice developed T-cell-dependent responses to TNP-OVA. These results were indicative of the adjuvant potential of these drugs. The present study set out to evaluate the nature of this adjuvant potential by focusing on early immune changes in the spleen, by testing several drugs in the same experimental model. Mice were exposed to one or multiple oral doses of previously-tested drugs: the non-steroidal-anti-inflammatory drug (NSAID) diclofenac (DF), the analgesic acetaminophen (APAP), the anti-epileptic drug carbamazepine (CMZ) or the antibiotic ofloxacin (OFLX). Within 24 h after the final dosing, early innate and also adaptive immune parameters in the spleen were examined. In addition, liver tissue was also evaluated for damage. Exposure to APAP resulted in severe liver damage, increased levels of serum alanine aminotransferase (ALT) and local MIP-2 expression. DF exposure did not cause visible liver damage, but did increase liver weight. DF also elicited clear effects on splenic innate and adaptive immune cells, i.e. increased levels of NK cells and memory T-cells. Furthermore, an increase in plasma MIP-2 levels combined with an influx of neutrophils into the spleen was observed. OFLX and CMZ exposure resulted in increased liver weights, MIP-2 expression and up-regulation of co-stimulatory molecules on antigen-presenting cells (APC). The data suggested that multiple immune parameters were altered upon exposure to drugs known to elicit immunosensitization and that broad evaluation of immune changes in straightforward short-term animal models is needed to determine whether a drug may harbor the hazard to induce IDHR. The oral exposure approach as used here may be applied in the future as an immunotoxicological research tool in this type of evaluation. ARTICLE HISTORY

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“…Interestingly, the observed concentration range of protein-derived APAP-Cys in the 300 mg/kg treatment group (1-7 M) is fairly consistent with recent results obtained through an alternative approach for measuring a specific APAP protein adduct. Switzar et al [44] measured APAP-mouse serum albumin adducts by utilizing affinity chromatography, gel filtration, tryptic digestion, and LC-MS analysis. Despite this methodological variation and significant experimental differences (mouse strain and sex, APAP dosing route, biological matrix, and sample collection time), mouse serum samples collected 1 day after treatment with 300 mg/kg APAP had a mean concentration of approximately 2 M APAP-mouse serum albumin.…”

Section: Application To Mouse Model Samplesmentioning

confidence: 99%

Quantification of a biomarker of acetaminophen protein adducts in human serum by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: Clinical and animal model applications

Cook

King

Chang

et al. 2015

Journal of Chromatography B

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Identification and quantification of drug–albumin adducts in serum samples from a drug exposure study in mice

Cited by 15 publications

References 36 publications

Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: Dose–response, mechanisms, and clinical implications

Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: Dose–response, mechanisms, and clinical implications

Oral exposure to immunostimulating drugs results in early changes in innate immune parameters in the spleen

Quantification of a biomarker of acetaminophen protein adducts in human serum by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: Clinical and animal model applications

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