FEATURE ARTICLE
Statins: From Fungus to Pharma
The curiosity of biochemists, mixed with some obvious economic incentives, created a family of powerful cardiovascular drugs
Philip A. Rea
Blue Cheese's Cousin
When Endo returned to Sankyo in 1968, he was to bring together his lifelong passion for mycology and his newfound interests in lipid metabolism. He set out to explore whether inhibiting HMG-CoA reductase could decrease blood cholesterol levels. Although other researchers had the same thing in mind, Endo took a fungal angle. He speculated that there must be at least a few fungal species capable of elaborating compounds—niche-carving antimetabolites—that target HMG-CoA reductase to do battle with fungal competitors that require cholesterol-like compounds for survival.
By 1971, Endo and his Sankyo colleague Masao Kuroda had started their search for fungal compounds that interfered with cholesterol production—via HMG-CoA reductase—in rat-liver extracts. After two years spent painstakingly screening 6,000 microbial strains, Endo and Kuroda at last found two promising cultures. The first came from Pythium ultimum. It inhibited HMG-CoA reductase and decreased cholesterol levels in rats, but it was eventually shown to be extremely toxic to the liver.
The second, a true hit this time, came from Penicillium citrinum, a relative of the organism responsible for the blue in blue cheese and the fungal mats that grow on old oranges—surely a thrilling result if only because of Endo's admiration for Fleming's exploits with this genus more than 40 years previously. By purifying active compounds from 2,900 liters of filtered liquid drawn from P. citrinum cultures, Endo and Kuroda isolated compound ML-236B. This is the compound that became known as mevastatin, signifying a substance that stops (where "stat" suggests static, or not changing) mevalonic acid synthesis. Mevastatin is a structural analogue of HMG-CoA: It is able to dock onto the enzyme HMG-CoA reductase and obstruct HMG-CoA binding, thus preventing its conversion into mevalonic acid for the synthesis of cholesterol.
With such a potentially promising inhibitor in hand, Sankyo faced two make-or-break questions: Does mevastatin do what it should in vivo, and if so is it free of deleterious side effects? Endo started exploring these questions in depth with rats. Much to his dismay, he found that mevastatin was effective only in the short term. Over longer trials, even at relatively high doses, it produced no consistent effect. That was very bad news—news that could have easily brought work on this compound as a cholesterol-lowering drug to an abrupt end.
By chance, though, one of Endo's colleagues offered some hens for testing. Given the high levels of cholesterol in chicken eggs, these birds seemed perfect for studying this strategy for cholesterol reduction. So Endo and his colleagues fed egg-laying hens with commercial chicken feed supplemented with mevastatin and then measured their blood cholesterol levels. It worked—decreasing cholesterol by as much as 50 percent, while leaving body weight, food intake and egg production unaffected.
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