Linked Life Data

3139868

Source:http://linkedlifedata.com/resource/pubmed/id/3139868

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1988-11-18
pubmed:abstractText
Over 60% of the analgesic/antipyretic drug acetaminophen is eliminated by glucuronidation, which competes with a toxifying pathway involving cytochromes P-450-catalyzed bioactivation to a hepatotoxic reactive intermediate. A genetic deficiency of bilirubin UDP-glucuronyl transferase (GT) occurs in 5 to 7% of the population (Gilbert's disease, Crigler-Najjar syndrome) and this could predispose such people to acetaminophen hepatotoxicity. This hypothesis was evaluated in the homozygous Gunn rat, which is similarly deficient in GT, and the heterozygous Gunn rat, which has intermediary GT activity. Acetaminophen, 1 g/kg, was administered by gavage to animals 6 and 11 weeks of age, and age-matched Wistar rats as controls. Hepatic and renal cellular damage were assessed by respective increases in the peak plasma concentration of alanine aminotransferase and the blood urea nitrogen concentration, and confirmed by histological examination. Acetaminophen and metabolites were measured by high-performance liquid chromatography. Compared to Wistar controls, Gunn rats demonstrated up to a 110-fold greater hepatotoxic response to acetaminophen, with significantly lower production of the glucuronide conjugate and higher plasma concentrations of acetaminophen. Elevated acetaminophen concentrations correlated positively with both increased production of the acetaminophen-cysteine conjugate, reflecting bioactivation and hepatotoxicity. Older Gunn but not Wistar rats showed up to 26-fold more hepatotoxicity compared to their younger counterparts. In younger animals, heterozygotes demonstrated intermediary hepatotoxicity between homozygotes and Wistar controls. Hepatotoxicity was similar in the older heterozygotic and homozygotic Gunn rats, as was renal toxicity, which was enhanced 2- to 3-fold over controls. These results indicate that a genetic deficiency in bilirubin GT can be an important determinant of acetaminophen bioactivation and toxicity.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0022-3565
pubmed:author
pubmed:issnType
Print
pubmed:volume
247
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
323-31
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1988
pubmed:articleTitle
Deficiency in bilirubin UDP-glucuronyl transferase as a genetic determinant of acetaminophen toxicity.
pubmed:affiliation
Faculty of Pharmacy, University of Toronto, Canada.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't