Determinants of Aspirin Metabolism in Healthy Men and Women: Effects of Dietary Inducers of UDP-Glucuronosyltransferases

Abstract

Background/Aims: Interindividual variation in aspirin (ASA) metabolism is attributed to concomitant use of drugs or alcohol, urine pH, ethnicity, sex, and genetic variants in UDP-glucuronosyltransferases (UGT). Little is known about the effects of diet. Methods: We evaluated cross-sectionally whether urinary excretion of ASA and its metabolites [salicylic acid (SA), salicyluric acid (SUA) phenolic glucuronide (SUAPG), salicylic acid acyl glucuronide (SAAG) and salicylic acid phenolic glucuronide (SAPG)] differed by UGT1A6 genotype and dietary factors shown to induce UGT. Following oral treatment with 650 mg ASA, urine was collected over 8 h in 264 men and 264 women (21–45 years old). Results: There were statistically significant differences in metabolites excreted between sexes and ethnicities. Men excreted more SUA; women more ASA (p = 0.03), SA, SAAG and SAPG (p ≤ 0.001 for all). Compared to Caucasians, Asians excreted more ASA, SA and SAAG, and less SUA and SUAPG (p ≤ 0.03 for all); African-Americans excreted more SAAG and SAPG and less SUA (p ≤ 0.04). There was no effect of UGT1A6 genotypes. Increased ASA and decreased SUAPG excretion was observed with increased servings of vegetables (p = 0.008), specifically crucifers (p = 0.05). Conclusion: Diet may influence the pharmacokinetics of ASA, but effects may be through modulation of glycine conjugation rather than glucuronidation.

Differences in the Glucuronidation of Resveratrol and Pterostilbene: Altered Enzyme Specificity and Potential Gender Differences

“…These results entreat the incorporation of gender into future studies of resveratrol and pterostilbene metabolization. Furthermore, this conclusion is consistent with other reports of gender differences in the glucuronidation of aspirin 32) and emodin. 33) …”

Non-steroidal anti-inflammatory drugs and small cell lung cancer risk in the VITAL study

“…One explanation for our subgroup findings is chance. Alternatively, these results are consistent with evidence from studies in animals [15] and humans [14] that aspirin is metabolized differently between the sexes, due in part to differences in the activity of metabolizing enzymes including the Cytochrome P450 and UDP-Glucuronosyltransferase enzyme families, leading to greater bioavailability of aspirin in women [23]. Several of the same metabolizing enzymes for which effects differ by sex are also responsible for the metabolism of polycyclic aromatic hydrocarbons (PAH) found in cigarette smoke [24–26].…”

“…Due to sex differences in NSAID metabolism [14,15] and the risks of SCLC due to smoking [16], we hypothesized, a priori , that the association between NSAIDs and SCLC risk would be modified by sex and smoking status. We therefore stratified multivariable models on these factors.…”

Effect of common single-nucleotide polymorphisms in acetylsalicylic acid metabolic pathway genes on platelet reactivity in patients with diabetes

“…UGT1A6*2 contains 2 missense mutations in exon 1 that result in T181A and R184S amino-acid substitution. These substitutions may be critical for ASA efficacy and are associated with altered enzyme function [12,22]. Allele frequencies of 17–33% for this variant in predominantly Caucasian populations have been reported [11,13].…”

“…Several genetic variants that result in altered enzyme activity have been identified in the UGT1A family [11,12]. Polymorphisms within the genes coding for these enzymes may play a significant role in ASA pharmacokinetics and pharmacodynamics.…”