| UGT1A6 and UGT2B15 polymorphisms and acetaminophen conjugation in response to a randomized, controlled diet of select fruits and vegetables. | |
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MedLine Citation:
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PMID: 21666065 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Acetaminophen (APAP) glucuronidation is thought to occur mainly by UDP-glucuronosyltransferases (UGT) in the UGT1A family. Interindividual variation in APAP glucuronidation is attributed, partly, to polymorphisms in UGT1As. However, evidence suggests that UGT2B15 may also be important. We evaluated, in a controlled feeding trial, whether APAP conjugation differed by UGT1A6 and UGT2B15 genotypes, and whether supplementation of known dietary inducers of UGT (crucifers, soy, citrus), modulated APAP glucuronidation compared to a diet devoid of fruits and vegetables (F&V). Healthy adults (n=66) received 1000 mg APAP orally on days 7 and 14 of each two-week feeding period, and collected saliva and urine over 12 h. Urinary recovery of % APAP dose as free APAP was higher (P=0.02), and %APAP-glucuronide (APAPG) lower (P=0.004) in women. %APAP was higher among UGT1A6*1/*1 genotypes, relative to *1/*2 and *2/*2 (P=0.045). For UGT2B15, %APAPG decreased (P<0.0001) and %APAP-sulfate increased (P=0.002) in an allelic dose-dependent manner across genotypes from *1/*1 to *2/*2. There was a significant diet-by-UGT2B15-genotype interaction for APAPG-ratio (APAPG/total metabolites*100) (P=0.03), with *1/*1s having an approximately 2-fold higher F&V-to-basal-diet difference in response compared to *1/*2s and *2/*2s. Salivary APAP Cmax was significantly higher in women (P=0.0003), with F&V (P=0.003), and among UGT1A6*2/*2s and UGT2B15*1/*2s (P=0.02 and 0.002, respectively). APAP half-life was longer in UGT2B15*2/*2s with F&V (P=0.009). APAP glucuronidation was significantly influenced by UGT2B15*2 polymorphism, supporting a role in vivo for UGT2B15 in APAP glucuronidation, whereas the contribution of UGT1A6*2 was modest. Selected F&V known to affect UGT activity led to greater glucuronidation and less sulfation. |
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Authors:
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Sandi L Navarro; Yu Chen; Lin Li; Shuying S Li; Jyh-Lurn Chang; Yvonne Schwarz; Irena B King; John D Potter; Jeannette Bigler; Johanna W Lampe |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-6-10 |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: - ISSN: 1521-009X ISO Abbreviation: - Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-6-13 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Fred Hutchinson Cancer Research Center. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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