In a new collection of three Classics articles, The Journal of Biological Chemistry features the contributions of F. Peter Guengerich to the fields of drug development and toxicology through his pioneering studies of the cytochrome P450 enzymes.
Guengerich, now a JBC associate editor and professor at Vanderbilt University, was introduced to the heme-containing enzyme in the early 1970s as a postdoc at the University of Michigan. He then went on to build a research team at Vanderbilt that set out to address several mysteries shrouding its actions by purifying it from rat samples.
In the early 1980s, about 40 percent of candidate drugs failed because of adverse side effects. Guengerich soon realized that his team’s initial endeavors into rodent enzyme characterization would not be enough to explain the toxicity of drug candidates in the human body, so he was able to partner with a Nashville transplant agency to obtain human liver samples, for which specimen collection calls often came late in the night.
During those days, before the advent of recombinant DNA technology, his team had to work with liver microsomal preparations followed by traditional native enzyme purification and gas chromatography-mass spectrometry assays to characterize the human P450 enzymes. But Guengerich’s team eventually isolated four of the five most important human P450s, which catalyze about 90 percent of the oxidations leading to drug metabolism.
Their work was reported in the three successive JBC publications, which for the first time elucidated the body’s most powerful detoxicating enzymes and served as a platform to understand failure of drug candidates and the basis of adverse interactions.
The field of cytochrome P450 research has developed considerably over the past 40 years. Fifty-seven human forms are now known, with hundreds of genetic variations. Bioactivation by cytochrome P450s and understanding how to make intelligent decisions about the potential toxicity of candidate drugs at an early phase is one of the biggest challenges for the pharmaceutical industry today. None of these development efforts would have taken off without the efforts of the group led by Guengerich, who is still actively pursuing the fundamental biochemistry of these drug-metabolizing enzymes.
Aditi Das (firstname.lastname@example.org) is a Washington, D.C.-based science writer and research consultant at the National Institutes of Health and Maryland Biotech Center. Connect with her on LinkedIn.