Conjugated and unconjugated bilirubin were injected intravenously at different times into normal rats and homozygous, jaundiced Gunn rats. As was expected, Gunn rats did not excrete injected unconjugated bilirubin in the bile. After the intravenous injection of conjugated bilirubin into normal rats, approximately twice as much bilirubin appeared in the bile per 100 g of body wt within 10 min than after the injection of comparable amounts of unconjugated bilirubin. This difference probably reflects the time required for cellular uptake and conjugation of bilirubin prior to excretion. The maximal biliary bilirubin excretory rate in Gunn rats following the administration of conjugated bilirubin was 56±8.4 (S.D.) µg of bilirubin excreted/100 g body wt/min. This does not differ significantly from the maximal biliary bilirubin excretory rate observed in normal rats after infusions of either conjugated or unconjugated bilirubin. This demonstrates that conjugation alone does not limit metabolism of bilirubin by normal rat liver. These studies, when considered in the light of other investigations, suggest that the ability to excrete conjugated bilirubin is the limiting factor in metabolism of bilirubin by normal rat liver.

Microbes are nature’s chemists, capable of producing and metabolizing a diverse array of compounds. In the human gut, microbial biochemistry can be beneficial, for example vitamin production and complex carbohydrate breakdown; or detrimental, such as the reactivation of an inactive drug metabolite leading to patient toxicity. Identifying clinically relevant microbiome metabolism requires linking microbial biochemistry and ecology with patient outcomes. Here we present MicrobeFDT, a resource which clusters chemically similar drug and food compounds and links these compounds to microbial enzymes and known toxicities. We demonstrate that compound structural similarity can serve as a proxy for toxicity, enzyme sharing, and coarse-grained functional similarity. MicrobeFDT allows users to flexibly interrogate microbial metabolism, compounds of interest, and toxicity profiles to generate novel hypotheses of microbe-diet-drug-phenotype interactions that influence patient outcomes. We validate one such hypothesis experimentally, using MicrobeFDT to reveal unrecognized gut microbiome metabolism of the ovarian cancer drug altretamine.

Over-the-counter pharmaceutical compounds can serve as microbial substrates in wastewater treatment processes as well as in the environment. The metabolic pathways and intermediates produced during their degradation, however, are poorly understood. In this study, we investigate an anaerobic wastewater community that metabolizes naproxen via demethylation. Enriched cultures, established from anaerobic digester inocula receiving naproxen as the sole carbon source, transformed naproxen to 6-O-desmethylnaproxen (DMN) within 22 days. Continual enrichment and culture transfer resulted in consistent demethylation of naproxen with no loss of DMN observed. Methane was generated at 0.83 mmol per 1 mmol transformed naproxen. In addition to naproxen, the consortium readily demethylated syringic acid and vanillic acid. DNA analysis revealed a community of acetogenic bacteria and syntrophic acetate oxidizing archaea. Combined with the biotransformation data, this suggests the enriched consortium performs aromatic O-demethylation through a syntrophic relationship between specific acetogens, acetate oxidizers, and methanogens. The proposed model of carbon transfer through the anaerobic food web highlights the significance of linked community interactions in the anaerobic transformation of aromatic O-methyl compounds such as naproxen.

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