5-(3,4-Dihydroxyphenyl)--Valerolactone Is a Substrate for Human Paraoxonase: A Novel Pathway in Flavan-3-ol Metabolism

ScopeDietary flavan-3-ols are known to mediate cardiovascular benefits. Currently, it is assumed that the levels of flavan-3-ol catabolites detected in humans, 5-(3MODIFIER LETTER PRIME,4MODIFIER LETTER PRIME-dihydroxyphenyl)-& gamma;-valerolactone (& gamma;VL) and 5-(3MODIFIER LETTER PRIME,4MODIFIER LETTER PRIME-dihydroxyphenyl)-& gamma;-valeric acid (& gamma;VA), and their corresponding phase II metabolites, are determined exclusively by the action of the gut microbiome. However, a family of human proteins, paraoxonase (PON), can theoretically hydrolyze & gamma;VL metabolites into the corresponding & gamma;VAs. This study aims to determine if PON is involved in & gamma;VL and & gamma;VA metabolism in humans. Methods and resultsA rapid conversion of & gamma;VL into & gamma;VA is detected in serum ex vivo (half-life = 9.8 & PLUSMN; 0.3 min) that is catalyzed by PON1 and PON3 isoforms. Phase II metabolites of & gamma;VL are also reacted with PON in serum. Following an intake of flavan-3-ol in healthy males (n = 13), the profile of & gamma;VA metabolites detected is consistent with that predicted from the reactivity of & gamma;VL metabolites with PON in serum. Furthermore, common PON polymorphisms are evaluated to assess the use of & gamma;VL metabolites as biomarkers of flavan-3-ol intake. ConclusionPONs are involved in flavan-3-ol metabolic pathway in humans. PON polymorphisms have a minor contribution to inter-individual differences in the levels of & gamma;VL metabolites, without affecting their use as a nutritional biomarker.