Akira Endo, PhD, the Japanese microbiologist and biochemist known as the father of statins, died at the age of 90 on June 5. His research led to the discovery and rise of a class of drugs that revolutionized the prevention and treatment of cardiovascular diseases. This scientific journey began over half a century ago.
Inspired by Alexander Fleming
Born into a family of farmers in northern Japan, Dr. Endo was fascinated by natural sciences from a young age and showed a particular interest in fungi and molds. At the age of 10, he already knew he wanted to become a scientist.
He studied in Japan and the United States, conducting research at the Albert Einstein College of Medicine in New York City. He was struck by the high number of elderly and overweight individuals in the United States and realized the importance of developing a drug to combat cholesterol. It was upon his return to Japan, when he joined the Sankyo laboratory, that the development of statins began.
Inspired by Alexander Fleming, who discovered penicillin in the mold Penicillium, he hypothesized that fungi could produce antibiotics inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that produces cholesterol precursors.
After a year of research on nearly 3800 strains, his team found a known substance, citrinin, that strongly inhibited HMG-CoA reductase and lowered serum cholesterol levels in rats. The research was halted because of its toxicity to the rodents’ kidneys. “Nevertheless, the experience with citrinin gave us hope and courage to quickly discover much more effective active substances,” said Dr. Endo in an article dedicated to the discovery of statins.
First Statin Discovered
In the summer of 1972, researchers discovered a second active culture broth, Penicillium citrinum Pen-51, which was isolated from a sample of rice collected in a grain store in Kyoto.
In July 1973, they isolated three active metabolites from this mold, one of which was compactin, which had structural similarities to HMG-CoA, the substrate of the HMG-CoA reductase reaction.
In 1976, they published two articles reporting the discovery and characterization of compactin (mevastatin), the first statin.
Several Setbacks
Unfortunately, when Sankyo biologists assessed the effectiveness of compactin by giving rats a diet supplemented with compactin for 7 days, no reduction in serum cholesterol was observed.
Only later did an unpublished study show that the statin significantly decreased plasma cholesterol after a month of treatment in laying hens. The hypocholesterolemic effects of compactin were then demonstrated in dogs and monkeys.
However, researchers faced a second challenge in April 1977. Microcrystalline structures were detected in the liver cells of rats that had been fed extremely high amounts of compactin (over 500 mg/kg per day for 5 weeks). Initially deemed toxic, the structures were ultimately found to be nontoxic.
A phase 2 trial began in the summer of 1979 with very encouraging preliminary results, but in August 1980, clinical development of compactin was halted, as the drug was suspected of causing lymphomas in dogs given very high doses: 100 or 200 mg/kg per day for 2 years.
This suspicion also led to the termination of trials on another statin, the closely related lovastatin, which was discovered simultaneously from different fungi by the Merck laboratory and Dr. Endo in February 1979.