RGD Reference Report - Type 1 diabetic mice are protected from acetaminophen hepatotoxicity. - Rat Genome Database

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Type 1 diabetic mice are protected from acetaminophen hepatotoxicity.

Authors: Shankar, K  Vaidya, VS  Apte, UM  Manautou, JE  Ronis, MJ  Bucci, TJ  Mehendale, HM 
Citation: Shankar K, etal., Toxicol Sci. 2003 Jun;73(2):220-34. Epub 2003 Apr 15.
RGD ID: 2313685
Pubmed: PMID:12700423   (View Abstract at PubMed)
DOI: DOI:10.1093/toxsci/kfg059   (Journal Full-text)

Streptozotocin (STZ)-induced diabetic (DB) mice challenged with single ordinarily lethal doses of acetaminophen (APAP), carbon tetrachloride (CCl4), or bromobenzene (BB) were resistant to all three hepatotoxicants. Mechanisms of protection against APAP hepatotoxicity were investigated. Plasma alanine aminotransferase, aspartate aminotransferase, and liver histopathology revealed significantly lower hepatic injury in DB mice after APAP administration. HPLC analysis of plasma and urine revealed lower plasma t1/2, increased volume of distribution (Vd), and increased plasma clearance (CLp) of APAP in the DB mice and no difference in APAP-glucuronide, a major metabolite in mice. Interestingly, covalent binding of 14C-labeled APAP to liver target proteins; arylation of APAP to 58, 56, and 44 kDa acetaminophen binding proteins (ABPs); and glutathione (GSH) depletion in the liver did not differ between nondiabetic (non-DB) and DB mice in spite of downregulated hepatic microsomal CYP2E1 and 1A2 proteins in the DB mice, known to be involved in bioactivation of APAP. Compensatory cell division measured via 3H-thymidine pulse labeling and immunohistochemical staining for proliferating cell nuclear antigen (PCNA) indicated earlier onset of S-phase in the DB mice after exposure to APAP. Antimitotic intervention of liver cell division by colchicine (CLC) after administration of APAP led to significantly higher mortality in the DB mice suggesting a pivotal role of liver cell division and tissue repair in the protection afforded by diabetes. In conclusion, the resistance of DB mice against hepatotoxic and lethal effects of APAP appears to be mediated by a combination of enhanced APAP clearance and robust compensatory tissue repair.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Experimental Diabetes Mellitus  ISOCyp2e1 (Mus musculus)2313685; 2313685 RGD 
Experimental Diabetes Mellitus  IEP 2313685 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cyp2e1  (cytochrome P450, family 2, subfamily e, polypeptide 1)

Genes (Mus musculus)
Cyp2e1  (cytochrome P450, family 2, subfamily e, polypeptide 1)

Genes (Homo sapiens)
CYP2E1  (cytochrome P450 family 2 subfamily E member 1)


Additional Information