The discovery of sulfate conjugation arose from studies on the fate of benzene and its oxidation product, phenol. Staedeler1 had observed the presence of conjugated phenols in human and animal urine. Munk, who was fascinated by the ability of animals to oxidize benzene, followed up on the studies of Schultzen and Naunyn and ingested varying amounts of benzene and measured the amounts of "phenol-forming substance."2 He found a direct relationship between the amount of benzene ingested and the increase in "phenol-forming substance" present in the urine.
During his attempts to quantitate the fate of benzene in humans Munk and coworkers ingested 20 drops of benzene and then analyzed their urine for phenol-forming substance. They also noticed direct excretion of the ingested benzene: "Part of the benzene is excreted unchanged as a gas from the stomach. During the first 8 hr after ingestion we were frequently annoyed by hiccups which had the exquisite smell and taste of coal tar and therefore were rich in benzene vapors."3
In addition to phenol-forming substance others had observed the presence of indigo-forming substances in the urine characterized by the release of indigo-dyes upon acid hydrolysis. Eugen Baumann (pictured lower right) isolated the indigo-forming substance and found that upon hydrolysis, in addition to the indigo, he obtained an amount of sulfuric acid which had not been present prior to the hydrolysis.4
Baumann was able to isolate and characterize phenol sulfate from the urine of a patient who had been treated with phenol as an antiseptic. He went on to show that many substances could give rise to increased sulfate excretion in the urine, including catechol, bromobenzene, indole and aniline. The latter three compounds all required oxidation prior to conjugation.
Ref: 1Stadeler, G. Ann.Chem.Liebigs 77:17 (1851), 2Munk, I. Arch.Ges.Physiol.Pfluegers 12:146 (1876), 3Quoted in Conti, A. and Bickel, M.H.Drug Metabolism Reviews, 6:p.17 (1977), 4Baumann, E. Pfluger's Arch.Physiol.12:69 (1876)
Picture: E.Baumann-courtesy of Photo Deutsches Museum Munchen
10/2/2016 » 10/6/2016
The 21st International Symposium on Microsomes and Drug Oxidations
10/27/2016 » 10/28/2016
ISSX Workshop: Translating Preclinical Data to Human Clearance and Pharmacokinetics