Unprecedented Microbial Conversion of Biliverdin into Bilirubin-10-sulfonate

Abstract

Biliverdin (BV) possesses antioxidant and anti-inflammatory properties, with previous reports identifying protection against oxidant and inflammatory injury in animal models. Recent reports indicate that intra-duodenal administration of BV results in the formation of an uncharacterised metabolite, which is potently absorbed into the blood and excreted into the bile. This compound may be responsible for protection against inflammatory responses. This study aimed to identify novel, enterally-derived BV metabolites and determine the source of their metabolic transformation. Rat duodena and bacterial cultures of Citrobacter youngae were treated with BV and subsequently analysed via high performance liquid chromatography/high resolution tandem mass spectrometry to identify and characterise metabolites of BV. A highly abundant metabolite was detected in duodenal wash and bacterial culture supernatants with a 663.215 m/z (3 ppm mass accuracy) and a composition of C 33 N 4 O 9 H 36 S, which conformed to the predicted structure of bilirubin-10-sulfonate (BRS) and possessed a λ max of 440 nm. Bilirubin-10-sulfonate was then synthesized for comparative LCMS/MS analysis and matched with that of the biologically formed BV metabolite. This report confirms the formation of a previously undocumented metabolite of BV in mammals, indicating that a new metabolic pathway likely exists for BV metabolism requiring enteric bacteria, Citrobacter youngae . These data may have important implications with regard to understanding and harnessing the therapeutic efficacy of oral BV administration.

Acute bilirubin ditaurate exposure attenuates ex vivo platelet reactive oxygen species production, granule exocytosis and activation

“…Despite reported attenuation of platelet granule exocytosis and integrin upregulation, BRT did not perturb aggregation [43]. This is inconsistent with previous findings of inhibited aggregation following antioxidant exposure [12,17,44].…”

Biliverdin and bilirubin sulfonate inhibit monosodium urate induced sterile inflammation in the rat

“…administration of BV in rodents also leads to the formation of bilirubin-10-sulfonate (BRS) (20,21) , a novel antioxidant with the potential to confer protection against oxidative and, potentially, inflammatory processes. (20) Testing the anti-inflammatory therapeutic potential of these bile pigments clearly requires further in vivo investigation in models of sterile inflammation with clinical relevance to human inflammatory conditions in order to determine their potential physiological importance and their suitability as novel therapeutics. Gouty arthritis is a common clinically relevant sterile inflammatory condition, with many patient's disease being refractory to treatment.…”

Effects of Guava (Psidium guajava L.) Leaf Extract on the Metabolomics of Serum and Feces in Weaned Piglets Challenged by Escherichia coli

“…On one hand, it may be finally converted into biliverdin via a series of metabolic steps, leading to the accumulation of biliverdin in the gut ( Figure 5 ). The biliverdin generated in this process can protect the intestines from oxidants and inflammation ( 39 , 40 ). On the other hand, 5-aminolevulinic acid was also potentially absorbed into the blood, resulting in the high level of 5-aminolevulinic acid in the serum via glycine and serine metabolism ( Figure 6 ).…”