title: UGT1A6 and UGT2B15 polymorphisms and acetaminophen conjugation in response to a randomized, controlled diet of select fruits and vegetables.
abstract: Acetaminophen (APAP) glucuronidation is thought to occur mainly by UDP-glucuronosyltransferases (UGT) in the UGT1A family. Interindividual variation in APAP glucuronidation is attributed in part 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, and citrus) modulated APAP glucuronidation compared with a diet devoid of fruits and vegetables (F&V). Healthy adults (n = 66) received 1000 mg of APAP orally on days 7 and 14 of each 2-week feeding period and collected saliva and urine over 12 h. Urinary recovery of the percentage of the APAP dose as free APAP was higher (P = 0.02), and the percentage as APAP glucuronide (APAPG) was lower (P = 0.004) in women. The percentage of APAP was higher among UGT1A6*1/*1 genotypes, relative to *1/*2 and *2/*2 genotypes (P = 0.045). For UGT2B15, the percentage of APAPG decreased (P < 0.0001) and that of 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 × UGT2B15 genotype interaction for the APAPG ratio (APAPG/total metabolites × 100) (P = 0.03), with *1/*1 genotypes having an approximately 2-fold higher F&V to basal diet difference in response compared with *1/*2 and *2/*2 genotypes. Salivary APAP maximum concentration (C(max)) was significantly higher in women (P = 0.0003), with F&V (P = 0.003), and among UGT1A6*2/*2 and UGT2B15*1/*2 genotypes (P = 0.02 and 0.002, respectively). APAP half-life was longer in UGT2B15*2/*2 genotypes with F&V (P = 0.009). APAP glucuronidation was significantly influenced by the 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.
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109, USA.
authors.forename: Sandi L
authors.initials: SL
authors.lastname: Navarro
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Shuying S
authors.initials: SS
authors.lastname: Li
authors.forename: Jyh-Lurn
authors.initials: JL
authors.lastname: Chang
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schwarz
authors.forename: Irena B
authors.initials: IB
authors.lastname: King
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Jeannette
authors.initials: J
authors.lastname: Bigler
authors.forename: Johanna W
authors.initials: JW
authors.lastname: Lampe
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D000328:Adult; D000483:Alleles; D018592:Cross-Over Studies; D004032:Diet; D005260:Female; D018565:Food-Drug Interactions; D005638:Fruit; D005838:Genotype; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D012463:Saliva / Q000378:metabolism; D014675:Vegetables
chemical_list: D020719:Glucuronides; D000082:Acetaminophen; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase; C472000:UDP-glucuronosyltransferase 2B15, human