Xenobiotic Metabolism

Woven among the origins of drug metabolism research are the threads of some fascinating tales. Imagine what it was like to be the first to conceive of a metabolic pathway and to prove it using your own body as part of the experimental method? Consumption of benzoic acid, cinnamic acid, and phenol by researchers (and their dogs) in the 19th century precipitated more than the interesting crystals they found in their urine. It lead to an entirely new concept: the fact that chemical transformations could actually occur in the body. The mysticism of the early 1800’s, which ascribed bodily processes to a “vital flame” beyond human comprehension, began to crumble in the light of the new sciences such as organic chemistry and early metabolic studies.

Much of the early research evolved from a general interest in disease, and potential therapies involving chemical substances. It was the scourge of streptococcus that stimulated the hiring of physician Gerhard Domagk by I.G. Farbenindustrie in 1927. There was no cure for most other bacterial infections at that time. What we shrug off as “strep throat” today, was a child killer then. Domagk had served in hospitals during World War I, while still a young medical student, and was appalled at the lack of options available for the treatment of cholera, typhus and other bacterial diseases.

Consider the story of one six year old child in 1935, afflicted with a raging streptococcal infection induced by an innocent pin prick to the finger. The infection spread to the lymph nodes under her arm. Lancing and draining the pus fourteen times did not help and the only remaining alternative was to amputate the arm. Even such a drastic measure would probably not save her life.

Gerhard Domagk intervened. He administered a dose of an innocuous red dye, a material which had shown absolutely no inhibition of streptococcus on agar plates. The girl recovered completely. Her name was Hildegard Domagk and she was his only daughter.

How could Domagk conceive such a therapy when the conventional method of screening for antibiotic activity indicated that this compound (Prontosil) was useless? The answer lies in his use of laboratory animals. If he had not conducted experiments with mice, he would have lost a child. He would never have discovered that Prontosil was metabolized into another compound which was lethal to steptococcus. This finding led to an entire class of drugs which saved countless lives.

During World War II, the pressing need for effective antibiotics dictated a change in the in vivo screening methods used by Domagk’s employer. Animal testing was abandoned by I.G. Farben in favor of human testing, but the humans were not volunteers. Prisoners in concentration camps were intentionally infected with bacterial diseases such as gangrene, and then treated with new chemical compounds. Domagk’s possible participation in these experiments, even if unwillingly, was a source of controversy which haunted him long after the war ended. Yet, his contributions to medicine continued as he also developed the first effective chemotherapy for tuberculosis via the thiosemicarbazones and isoniazid.

The Nobel prize was awarded to three of the individuals profiled in this calendar. Lipmann elucidated the role of Coenzyme A while studying sulfanilamides. Domagk’s discovery of Prontosil merited the award which he was forced to reject in 1939 by the Nazi government. Axelrod was working as a technician in a food safety laboratory when he was asked to determine why his fellow citizens of New York were turning blue. His quest for the source of their cerulean pallor put him in contact with Bernard Brodie at NIH. Together they determined that acetanilide in a popular analgesic was metabolized to aniline, which elicited methemoglobinemia and a very literal case of “the blues”. More importantly, they also discovered another metabolite which was safer and a more effective pain reliever (now known as acetaminophen). This work inspired Axelrod to pursue a doctoral degree and eventual employment at NIH, where he later conducted studies on the reuptake mechanism of catecholamine neurotransmitters and earned his Nobel prize.

Science teachers should harken to the tales told by Bernard Brodie, who recalled the academic apathy of his youth, and the profound disappointment of those who tried hard to teach him. One chemistry teacher refused to give him a recommendation for a summer job, and he dropped out of high school after arguing with the principal. While in the Canadian army (where he distinguished himself as a boxer) he won enough money playing poker to enroll in McGill University. There he remembered routinely falling asleep during chemistry class. Yet it was ultimately a chemistry professor who awoke in Brodie a passion for developing accurate and reliable methods of biomedical analysis. This culminated in a very distinguished career at NIH, where his many contributions in the fields of drug metabolism and bioanalytical chemistry were described as “brilliant”.