Journal article
The UDP-glucuronosyltransferase (UGT) 1A polymorphism c.2042C>G (rs8330) is associated with increased human liver acetaminophen glucuronidation, increased UGT1A exon 5a/5b splice variant mRNA ratio, and decreased risk of unintentional acetaminophen-induced acute liver failure
The Journal of pharmacology and experimental therapeutics, Vol.345(2), pp.297-307
05/2013
Handle:
https://hdl.handle.net/2376/101343
PMID: 23408116
Abstract
Acetaminophen is cleared primarily by hepatic glucuronidation. Polymorphisms in genes encoding the acetaminophen UDP-glucuronosyltransferase (UGT) enzymes could explain interindividual variability in acetaminophen glucuronidation and variable risk for liver injury after acetaminophen overdose. In this study, human liver bank samples were phenotyped for acetaminophen glucuronidation activity and genotyped for the major acetaminophen-glucuronidating enzymes (UGTs 1A1, 1A6, 1A9, and 2B15). Of these, only three linked single nucleotide polymorphisms (SNPs) located in the shared UGT1A-3'UTR region (rs10929303, rs1042640, rs8330) were associated with acetaminophen glucuronidation activity, with rs8330 consistently showing higher acetaminophen glucuronidation at all the tested concentrations of acetaminophen. Mechanistic studies using luciferase-UGT1A-3'UTR reporters indicated that these SNPs do not alter mRNA stability or translation efficiency. However, there was evidence for allelic imbalance and a gene-dose proportional increase in the amount of exon 5a versus exon 5b containing UGT1A mRNA spliced transcripts in livers with the rs8330 variant allele. Cotransfection studies demonstrated an inhibitory effect of exon 5b containing cDNAs on acetaminophen glucuronidation by UGT1A1 and UGT1A6 cDNAs containing exon 5a. In silico analysis predicted that rs8330 creates an exon splice enhancer site that could favor exon 5a (over exon 5b) utilization during splicing. Finally, the prevalence of rs8330 was significantly lower (P = 0.027, χ(2) test) in patients who had acute liver failure from unintentional acetaminophen overdose compared with patients with acute liver failure from other causes or a race- or ethnicity-matched population. Together, these findings suggest that rs8330 is an important determinant of acetaminophen glucuronidation and could affect an individual's risk for acetaminophen-induced liver injury.
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Details
- Title
- The UDP-glucuronosyltransferase (UGT) 1A polymorphism c.2042C>G (rs8330) is associated with increased human liver acetaminophen glucuronidation, increased UGT1A exon 5a/5b splice variant mRNA ratio, and decreased risk of unintentional acetaminophen-induced acute liver failure
- Creators
- Michael H Court - Comparative and Molecular Pharmacogenomics Laboratory, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, 100 Grimes Way, Pullman, WA 99164, USA. michael.court@vetmed.wsu.eduMarina FreytsisXueding WangInga PeterChantal GuillemetteSuwagmani HazarikaSu X DuanDavid J GreenblattWilliam M Lee
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.345(2), pp.297-307
- Academic Unit
- Veterinary Clinical Sciences, Department of
- Publisher
- United States
- Grant note
- U01-DK58369 / NIDDK NIH HHS N01-DK-7-0004 / NIDDK NIH HHS U01 DK058369 / NIDDK NIH HHS R01-GM061834 / NIGMS NIH HHS MOP-84223 / Canadian Institutes of Health Research MOP-42392 / Canadian Institutes of Health Research R01 GM102130 / NIGMS NIH HHS R01 GM061834 / NIGMS NIH HHS
- Identifiers
- 99900546557601842
- Language
- English
- Resource Type
- Journal article