A Gift from Nature: the Birth of the Statins
Total Page：16
File Type：pdf, Size：1020Kb
LASKER~DEBAKEY C L INICA L M E D ICA L COMMENTARY RESEARCH AWARD A gift from nature: the birth of the statins Akira Endo I was born into a rural farming family in study under him. Unfortunately, the autumn northern Japan, near Akita, where I lived for 1966 class for which I was applying was already 17 years with my extended family, including full. So I eventually studied from September grandparents, parents, three brothers and two 1966 to August 1968 at the Department of sisters. My grandfather, who had an interest Molecular Biology at the Albert Einstein College in medicine and science, was a great home of Medicine in New York. Under the guidance teacher to me. Thanks to his influence, at the of Bernard Horecker and Lawrence Rothfield, age of 8, I dreamt of becoming a scientist, I studied an enzyme that was involved in the much like the renowned Japanese scientist biosynthesis of bacterial cell wall lipopolysac- Hideyo Noguchi, who, in 1900 at the age of 24, charide. The outcome of my research depended went to the United States and studied syphilis upon purifying the unstable enzyme. A year and yellow fever at the Rockefeller Institute into the project, I succeeded and showed that in New York. the formation of an enzyme–phospholipid After finishing high school in Akita, I entered complex was crucial for its action. Tohoku University’s College of Agriculture in While living in New York, I was very sur- Sendai in 1953. I excelled in organic chemis- prised by the large number of elderly and over- try at high school. So, in addition to study- weight people, and by the rather rich dietary ing organic chemistry at the university, I also habits of Americans compared to those of the chose biochemistry and applied microbiology Japanese. In the residential area of the Bronx as my preferred subjects. At that time, many where I lived, there were many elderly couples drug companies and universities in Japan were living by themselves, and I often saw ambu- Figure 1 Micrograph of Penicillium citrinum conducting active research and development lances coming to take an elderly person who Pen-51, the fungus that produces compactin. in finding effective antibiotics. As a student, I had suffered a heart attack to the hospital. Scale bar, 10mm. was deeply impressed by the knowledge that At that time, coronary heart disease was the antibiotics had saved the lives of many patients main cause of death in the United States. The been developed. My experience of living in with infectious diseases. number of people with hypercholesterolemia, New York made me realize the importance Upon graduating in 1957, I joined the phar- a precursor to coronary heart disease, was said of developing a cholesterol-lowering drug. maceutical company Sankyo in Tokyo, where to exceed 10 million. In August 1968, I finished my studies in the I was assigned to one of the applied microbi- Cholesterol in the body comes from what United States and returned to Sankyo to con- ology groups. I worked toward developing a is absorbed from diet and from what is syn- tinue to work on this problem. new pectinase that hydrolyzes viscid pectin thesized in the body, mainly by the liver. In contaminating wines and ciders. In 1958 I the 1960s it was shown that, in humans, cho- Discovering compactin from blue-green found a grape-parasitic fungus, Coniothyrium lesterol produced in the liver exceeds what mold diplodiella, to be a potent producer of such an is absorbed from the diet. 3-Hydroxy-3- In 1971, I speculated that microbes would enzyme. I then purified it and elucidated its methylglutaryl (HMG)-CoA reductase, an produce antibiotics that inhibited HMG-CoA properties. For these studies, I received a PhD enzyme that catalyzes the conversion of HMG- reductase as a defense mechanism against degree from Tohoku University in 1966. CoA into mevalonate, proved to be the rate- other microbes that require sterols and/or At this point, I became interested in choles- controlling enzyme in cholesterol synthesis. other mevalonate-derived isoprenoids for terol biosynthesis. Toward the end of 1965 I On the basis of these facts, I speculated that a their growth, and we created a research unit wrote a letter to Konrad Bloch, who had received cholesterol-synthesis inhibitor, particularly a to isolate such products, focusing on fungi as a the Nobel Prize for his research on cholesterol HMG-CoA reductase inhibitor, would be an source of these metabolites. biosynthesis in 1964, expressing my wish to effective cholesterol-lowering agent. The search for a suitable compound took 2 In the 1960s, a number of lipid-lowering years and involved 6,000 strains of microbe. Akira Endo is at Biopharm Research Laboratories, agents, such as clofibrate, niacin and chole- Initially, we looked for microbial culture Inc., 3-41-3 501 Shimorenjaku, Mitaka, Tokyo 181- stylamine, were available, but none of them broths that would inhibit the incorporation 0013, Japan. were considered safe and effective. Moreover, of 14C-acetate into sterols. We then tested cul- e-mail: [email protected] a HMG-CoA reductase inhibitor had not yet ture broths that had shown inhibitory activity xxiv VOLUME 14 | NUMBER 10 | OCTOBER 2008 NATURE MEDICINE COMMENTARY work in rats was the abnormal induction of at more than ten hospitals. All of the par- – – HMG-CoA reductase3. ticipating hospitals reported positively on the In the early spring of 1976, Noritoshi Kitano, remarkable efficacy and excellent safety profile a pathologist at Sankyo who was keeping laying of compactin. hens for research purposes, kindly agreed to In August 1980, Sankyo held a meeting a joint research project to evaluate compactin with the physicians involved in the trials using his hens. The experiments were a great to announce the suspension of the clinical success. The plasma cholesterol of laying hens development of compactin, which had been that received compactin decreased by 34% after progressing smoothly. Although the detailed 2 weeks. Soon after, we were able to confirm the reasons for this decision were not revealed, we profound cholesterol-lowering effects of com- all considered it to be the result of compactin 4,5 Figure 2 A comparison of the structures of four pactin in dogs and monkeys . These results experiments in dogs. In these long-term toxic- statins and mevalonate. defined compactin as a candidate for a new ity experiments, in which dogs were given com- type of drug. So, the ‘Compactin Development pactin for 2 years, no abnormalities were noted Project’—headed by myself and including in the group receiving 25 mg/kg/d. However, in that assay to see if they would inhibit the pharmacologists, pathologists, toxicologists, lymphomas were detected in the group receiv- production of sterols from 3H-mevalonate. organic chemists and applied microbiolo- ing 100 or 200 mg/kg/d. In long-term toxicity Broths active in the first screen but not in gists—was launched in August 1976. experiments on dogs for pravastatin (a drug the second were deemed to be inhibitors in Interestingly, at around the same period, developed later and discussed below), Sankyo the early part of cholesterol synthesis. Broths researchers from England’s Beecham lowered the maximum dose to 25 mg/kg/d; from two fungi met our requirements. The Laboratories had also discovered compactin as there was no mention of any 100 or 200 mg/ first fungus, Pythium ultimum ML-145, pro- an antibacterial agent from another blue-green kg/d group5. So, it seems that, regardless of duced citrinin (a known antifungal agent) mold (Penicillium brevicompactum). However, whether lymphomas were actually detected or as the active principle. The second fungus, they were unable to develop the HMG-CoA not, Sankyo could have continued the develop- Penicillium citrinum Pen-51, was a blue- reductase inhibitor as a cholesterol-lowering ment of compactin by limiting its maximum green mold isolated from the rice of a vendor agent due to the inability of compactin to lower dose to 25 mg/kg/d. (I retired from Sankyo in Kyoto in the 1960s (Fig. 1). We isolated the blood cholesterol of rats and mice as, con- at the end of 1978 and joined Tokyo Noko the inhibitory compound from P. citrinum sistent with our findings, it strongly induced University in January 1979.) Pen-51 broths—ML-236B (now known as the HMG-CoA reductase of the liver6. compactin)—by solvent extraction, silica gel We encountered a second challenge in April The arrival of Merck chromatography and crystallization. 1977. The issue was the detection of microcrys- In the summer of 1976, Sankyo and Merck We soon realized the structural similari- talline structures in the liver cells of rats that entered into a contract for the disclosure ties between compactin and mevalonate, the had been fed extremely large amounts of com- of information on compactin. Until the product of the HMG-CoA reductase reac- pactin (more than 500 milligrams per kilogram autumn of 1978, Sankyo continued to pro- tion. The structure compactin was exactly body weight per day (mg/kg/d)) for 5 weeks. vide experimental data on biochemistry, as we had previously envisioned (Fig. 2)1. The toxicologists insisted that these structures drug efficacy, pharmacology and pathology, Compactin was a potent inhibitor of HMG- were toxic substances. It took us 9 months to along with compactin crystals, to Merck. CoA reductase, and its mechanism of action, identify these microcrystalline structures as We were, in fact, under the impression that suggested by its structure, was that of a com- nontoxic cholesterol. both companies were jointly developing petitive inhibitor2. I had had my sights set In August 1977, Akira Yamamoto from Osaka on finding a competitive inhibitor of HMG- University Hospital inquired about using com- CoA reductase, and compactin seemed to be pactin in the treatment of a homozygous patient a wonderful gift from nature.