Acetaminophen adducts and methods of use thereof

• US 10,351,897 B2
• Filed: 02/13/2015
• Issued: 07/16/2019
• Est. Priority Date: 02/14/2014
• Status: Active Grant

• Current Assignee: Arkansas Children's Hospital Research Institute Inc., Bioventures, LLC
• Original Assignee: Bioventures, LLC
• Inventors: James, Laura P., Hinson, Jack, Roberts, Dean, Gill, Pritmohinder S.
• Primary Examiner(s): Haq, Shafiqul
• Application Number:
  US15/118,297
• Publication Number:
  US 20170175166A1
• Time in Patent Office: 1,614 Days
• CPC Class Codes: C07K 14/4708 Duchenne dystrophy
• CPC Class Codes: C12N 9/1007 Methyltransferases (general) (2.1.1.)
• CPC Class Codes: C12N 9/1014 Hydroxymethyl-, formyl-transferases (2.1.2)
• CPC Class Codes: C12N 9/107 1,4-Alpha-glucan branching enzyme (2.4.1.18)
• CPC Class Codes: C12N 9/1096 transferring nitrogenous groups (2.6)
• CPC Class Codes: C12Q 1/48 involving transferase
• CPC Class Codes: C12Q 1/527 involving lyase
• CPC Class Codes: C12Y 201/01005 Betaine--homocysteine S-methyltransferase (2.1.1.5)
• CPC Class Codes: G01N 2333/91017 with definite EC number (2.1.1.-)
• CPC Class Codes: G01N 2333/91131 Glucan branching enzymes (2.4.1.18)
• CPC Class Codes: G01N 2333/91188 transferring nitrogenous groups (2.6)
• CPC Class Codes: G01N 2333/988 Lyases (4.), e.g. aldolases, heparinase, enolases, fumarase
• CPC Class Codes: G01N 2800/085 Liver diseases, e.g. portal hypertension, fibrosis, cirrhosis, bilirubin
• CPC Class Codes: G01N 2800/709 Toxin induced
• CPC Class Codes: G01N 33/53 Immunoassay; Biospecific binding assay; Materials therefor
• CPC Class Codes: G01N 33/573 for enzymes or isoenzymes
• CPC Class Codes: G01N 33/94 involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors

Abstract

The present disclosure relates to acetaminophen protein adducts and methods of diagnosing acetaminophen toxicity using the acetaminophen protein adducts. The present disclosure provides acetaminophen (APAP)-protein adducts and methods of detecting acetaminophen-induced toxicity in a subject using APAP-protein adducts. One aspect of the present disclosure provides an APAP-protein adduct for diagnosing acetaminophen-induced toxicity. According to the present disclosure, the inventors have identified proteins that are modified by N-acetyl-pbenzoquinoneimine (NAPQI) in subjects with acetaminophen-induced toxicity. Non-limiting examples of proteins modified by NAPQI include betaine-homocysteine S-methyltransferase 1, cytoplasmic aspartate aminotransferase, 1,4-alpha-glucan branching enzyme, formimidoyltransferase-cyclodeaminase, and dystrophin.

Claims

1. A method of treating acetaminophen-induced toxicity in a subject in need thereof, the method comprising:

a) obtaining a biological sample from the subject;

b) measuring the amount of acetaminophen (APAP)-protein adduct in the sample by detecting one or more APAP-protein adducts, wherein each APAP-protein adduct comprises a protein covalently modified with N-acetyl-p-benzoquinone (NAPQI), and wherein the protein is selected from the group consisting of betaine-homocysteine S-methyltransferase 1, cytoplasmic aspartate aminotransferase, 1,4-alpha-glucan-branching enzyme, formimidoyltransferase-cyclodeaminase, and dystrophin;

c) comparing the measured amount of the acetaminophen-protein adduct in the sample to a reference value, wherein a greater amount of acetaminophen-protein adduct in the sample compared to the reference value indicates acetaminophen-induced toxicity in the subject; and

d) administering treatment for acetaminophen-induced toxicity after step c) to the subject.

2. The method of claim 1, wherein the acetaminophen-induced toxicity is directly or indirectly associated with acetaminophen overdose.

3. The method of claim 1, wherein the acetaminophen-induced toxicity is hepatotoxicity.

4. The method of claim 1, wherein the biological sample is a biological fluid selected from the group consisting of blood, plasma, serum, urine, saliva and hair.

5. The method of claim 1, wherein the biological sample is from a subject with hepatotoxicity of unknown etiology.

6. A method of treating acetaminophen-induced toxicity in a subject in need thereof, the method comprising:

a) obtaining a sample from the subject;

b) measuring the amount of acetaminophen (APAP)-protein adduct in the sample to determine a profile of APAP-protein adducts in the subject, the profile comprising the identity and concentration in the sample from the subject of one or more APAP-protein adducts, wherein each APAP-protein adduct comprises a protein covalently modified with N-acetyl-p-benzoquinone (NAPQI), and wherein the protein is selected from the group consisting of betaine-homocysteine S-methyltransferase 1, cytoplasmic aspartate aminotransferase, 1,4-alpha-glucan-branching enzyme, formimidoyltransferase-cyclodeaminase, and dystrophin;

c) comparing the profile determined in (b) to a database comprising the presence and concentration of one or more APAP-protein adducts correlated with acetaminophen toxicity;

d) identifying a matching entry of the database in which the identity and concentration of the one or more APAP-protein adducts matches the identity and concentration of the one or more APAP-protein adducts in the sample;

e) determining the acetaminophen toxicity comprising the particular acetaminophen toxicity of the matching entry; and

f) administering treatment for acetaminophen-induced toxicity after step e) to the subject.