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UGT1A6 gene polymorphism and in vivo aspirin metabolism
Author(s) -
Chen Yu,
Kuehl Gwendolyn E.,
Bigler Jeannette,
Rimorin Christine F.,
Schwarz Yvonne,
Shen Danny D.,
Lampe Johanna W.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a265-b
Subject(s) - glucuronide , chemistry , metabolism , aspirin , pharmacokinetics , metabolite , urine , genotype , medicine , endocrinology , pharmacology , biochemistry , gene
Aspirin (acetyl salicylic acid, ASA) is rapidly deacetylated to form salicylic acid (SA) in the body. SA is further metabolized by glycine and glucuronide conjugation. UDP‐glucuronosyltransferases (UGTs) catalyze glucuronide conjugation of SA. Observational studies suggest that UGT1A6 *2/*2 (T181A, R184S) is associated with lower risk of colon adenoma among aspirin users. Our objective was to compare SA metabolism in individuals with the UGT1A6 *1/*1 (n = 19) and UGT1A6 *2/*2 (n = 9) genotypes. After dosing with 650 mg aspirin, participants collected saliva and urine samples for 24 hours. There were no statistically significant differences in salivary pharmacokinetic parameters; however, UGT1A6 *1/*1 individuals tended to have longer elimination half life, higher area under curve and slower clearance of SA compared to UGT1A6 *2/*2 individuals. Urinary excretion (% of dose administered) of ASA and its metabolites (salicyluric acid + salicyluric acid phenolic glucuronide + salicyl phenolic glucuronide + salicyl acyl glucuronide + SA) during the early period of 2– 4 hours was significantly lower in UGT1A6 *1/*1 vs UGT1A6 *2/*2 individuals, 16.1% ± 1.0 and 23.9% ± 1.7, respectively (p < 0.05). Also, individuals with the UGT1A6 *1/*1 genotype excreted a lower percentage of ASA metabolites in the first 8 hours and a greater percentage after 8 hours compared to those individuals with the UGT1A6 *2/*2 genotype. These results suggest that the homozygous variant UGT1A6 *2/*2 may confer more rapid metabolism of SA compared to the wild type UGT1A6 *1/*1, or that other polymorphic UGTs in linkage disequilibrium might also play a role. Supported by R01 CA92288 and T32 CA77116 (GEK).