Xenobiotic Metabolism

Felix Hoppe-Seyler

Gerhard Domagk

Reduction

The process of enzymatic reduction was responsible for one of the greatest advances in human medicine—and a significant change in how drug metabolism was perceived.

The history began in 1863 with E. Lautemann who noted how readily quinic acid converted to benzoic acid in the test tube. He and his colleagues each ingested 8 grams of calcium quinate and collected urine while determining whether this effect was also mediated by human metabolism. They found hippuric acid in all three samples.

Felix Hoppe-Seyler (Eugen Baumann’s professor) published the first definitive study in 1882, indicating that the body could reduce nitro groups to corresponding amines. He isolated indoxylsulfate after administration of o-nitrophenylpropiolic acid and presumed that the initial reaction was conversion of the nitro group to a primary amine.

It was the research of Gerhard Domagk which energized the world of drug metabolism, and yielded a product with benefits for all of humanity. In 1932, he joined a team of industrial researchers seeking a treatment for streptococcal infections. Using a series of sulfonamide compounds which had shown poor activity against streptococcal cultures in vitro, he dosed mice 1.5 hours after they had been infected. The controls died rapidly, while the mice treated with 2',4'-diaminoazobenzene-4'-sulfonamide (Prontosil) lived. His work was published in 1935, and led to the development of the “sulfa” drugs, which provided the first effective treatment for acute bacterial infection. Later that year, Trefouel and co-workers in France found that the diazo link of Prontosil was not required for therapeutic efficacy and speculated that the active principle could be formed by reduction of the diazo bond, yielding p-aminobenzenesulfonamide.

The following year, A.T. Fuller, working in Colebrook’s laboratory in London, provided the proof that aminobenzenesulfonamide was present in urine and blood after dosing with Prontosil. Colebrook and Kenny logged the progress of puerperal (“child-bed”) fever cases after treatment with Prontosil. The break in the fever was as dramatic as the disappearance of streptococcus in the blood culture. This infection was a leading cause of death among women after childbirth and was highly contagious.

Background image: A chart from Colebrook illustrates the drop in body temperature for a puerperal fever patient after treatment with Prontosil.

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