Diosgenin Production in North America, a Brief History

Diosgenin Production in North America A Brief History Ray F. Dawson1 Additional index words. steroid hormones, cortisone, fertility regulants, synthesis intermediates, progesterone, Mexican yam, Dioscorea cultivation, low-tension soil water, stigmasterol, sitosterol Summary. Diosgenin is a steroidal aglycone occurring in certain species of Dioscorea native principally to eastern Mexico. In the 1940s, diosgenin became a much-sought-after intermediate for the chemical synthesis of certain corticosteroids and structurally related fertility regulants. Various difficulties of access to native sources led to attempts at plantation production. One of these, supported by the Upjohn Company between 1962 and 1980, was located on the Pacific coast of Guatemala and is described herein from the standpoint of technology development. The Dioscorea plant produces a long, coarse vine that requires support. The deep-growing, fleshy rhizome contains the diosgenin and, at harvest, must be removed from soil depths up to 1 m. Dry rhizome yield depends on supply of readily available (low-tension) soil water. Sites located over abundant water reserves give satisfactory rhizome yields, but diosgenin concentrations fall to uneconomically low levels under such circumstances. By 1980, diosgenin had been displaced by two products of soya oil processing, stigmasterol and sitosterol, which became available as a result of advances in microbial fermentation technology. Consequently, the cultivation of Dioscorea was abandoned. he recent history of diosgenin pro- synthesis intermediate in the pharmaceutical duction and use is marked by an industry for almost 40 years. During those unusual convergence of interests years, great quantities were extracted from T ranging from industrial botany the rhizomes (root or tuber in trade parlance) through medicine, pharmaceutical chemia- of Dioscorea spp. native to and collected from try, business, and international politics. It is a the wild in eastern Mexico. Various pressures tale of extremes. Need for diosgenin arose led to attempted cultivation of some of these precipitously in the 1940s, when no com- species on plantations. Perhaps the most mercial source existed. It remained a favored comprehensive and long-lived effort was that of the Upjohn Company in Guatemala. Un- der intensive cultivation, allowances had to 1Consultant in tropical agriculture (retired). 40 Palmer Avenue, be made for support of the long (up to 30 m) Winter Park, FL 32789. woody vines and for removal of rhizomes 22 American Society for Horticultural Science from soil depths up to 1 m at harvest. The required. The small amounts then available most exacting site requirement was for a were said to be under monopolistic control continuous and abundant source of low- by three European manufacturers (see Senate tension soil water. Eventually, diosgenin lost Hearings, 1956). Only 3 years ahead of the its preferred position, so far as the Upjohn crisis of supply, Marker et al. (1947) devised Company was concerned when stigmasterol a synthesis ofprogesterone , the corpus luteum and sitosterol became accessible microbially hormone, from diosgenin. On a hunch forthe preparation of avarietyof commercially (Marker, 1987), he explored the Dioscoreaceae useful steroid intermediates. As so often of eastern Mexico, where he found substan- happens, displacement of a reigning botani- tial quantities of diosgenin-containing raw cal resulted from advances in industrial mi- material. His successes in both chemical and crobiology and in organic chemistry. But, plant exploratory facets of this field have won while demand remained high, it would be for him far greater attention in Mexico difficult to name a more-challenging project (Lehmann et al., 1973) in the field of industrial botany than was the than they have in his attempted cultivation in the American tropics native land. He ex- of the Mexican yam, Dioscorea composita tracted diosgenin from Hems!' (Matuda, 1953) and its variants. the woody rhizomes of a Diosgenin isfound in the st<?rageorgans the "cabeza de negro," (rhizomes) of certain species of Dioscorea that Dioscorea mexicana occur in Mexico and adjacent Guatemala. Guillemin, and pre- Chemically,diosgenin isthe steroidal aglycone pared from it 3 kg of (Fig. 1), released upon acid hydrolysis, of a .progesterone (Marker, saponaceous glycoside, dioscin. Dioscin- 1987), by far the larg- Fig. l.Diol8enin. containing plant parts, when macerated in est quantity ever before water, impart a surfactant property that the seen. Marker had not long to wait. In 1949, indigens of Mexico and Central America two developments in medicine set off the employed for cleaning purposes. The starchy explosive demand that he had foreseen. From rhizomes were eaten, albeit without relish, in the Mayo Clinic there came an announce- seasons of maize crop failure (de Landa, ment of the dramatic effect of administered medi- 1566). Dioscin is also hemolytic (Coursey, cortisone upon symptoms of rheumatoid ar- terol, 1967). Pre-Columbian inhabitants of the re- thritis. And, from the Worcester Inst. for gion dispersed pulped rhizomes in slowly Developmental Biology, came the first prac- moving streams, whereupon fish suffocated, tical fertility regulants. Although the earliest ltive floated to ,ermedi- the surface, and could be retrieved intermediates for cortisone synthesis were the easilyby hand. r The archeological museum at steroidal bile acids, both cortisone and the ~roduc- the Tikal ruins in Guatemala contains an fertility regulants could be made, at that time, located incised bone depiction of a Mayan fishing much more easily from diosgenin. Conse- lology party removing very limp fish from foam- quently, a world -wide search began for abun- Che covered waters. More recently, North Ameri- dant and inexpensive supplies of intermedi- lfrom canpatent medicines of the late 19th and early ates, including diosgenin, that could be used :ension) 20th centuries made use of dioscin-contain- advantageously for the manufacture of desired but ing extracts in the concoction of remedies for ay 1980, steroid compounds (for two interesting ex- "female troubles," but uses still to come amples, see Landrum, 1986). sitos- could not have been foreseen logy. by either stone- Total synthesis of steroids from the age Maya or our forebearers. simplest organic compounds was still years in Diosgenin was isolated first from the the future-and that route would be pro- rhizomes of anAsiaticspecies,Dioscorea tokoro hibitively expensive in any case. In the words Makino (Tsukamotoetal., 1936). Fouryears of George Pucher, at one time of the Con- later, R.E. Marker (1940a, 1940b, 1943), of necticut Agricultural Experiment Station, laceutical the Pennsylvania State College, published New Haven, the plant world came to be ing those the molecular structure and botanical occur- regarded as a storehouse of rare chemicals, :ted from rences of this aglycone. Marker's interest and it was ransacked from top to bottom in parlance) went far beyond the academic to the realm of search of ever more useful intermediates. ctedfrom prescience. At that time, knowledge of the Marker scored a third time by discovering, pressures chemistry and physiology of mammalian hor- alsoin eastern Mexico, enormous populations Ieofthese mones was expanding rapidly. Research of Dioscorea composita Hems!., known locally the most quantities were needed of those constituents as "barbasco," a far more tractable source of 1:wasthat of the animal body that, up to that time, had diosgenin than was D. mexicana. Mexican mala.Un- been known only in trace amounts. Should resources began to be "mined" by rhizome :eshad to therapeutic uses emerge, Marker reasoned, collectors. Mexican authorities estimated that )to 30 m) the pharmaceutical industry would be wholly the states of Vera Cruz and Oaxaca alone rhizomes unprepared to produce the bulk quantities contained up to 25 t of dry root equivalent! :ural Science HortTechnology.Oct/Dec. 1991 23 km2, and that » 5500 t of air-dried mate- bunda Mart et Gal., a less vigorous species rial was then being removed annually (Senate possessing a higher average diosgenin con- Hearings, 1956). Giral (1958) stated that the tent (» 5%) and recognized by the yellow flesh diosgenin concentration in this material of its rhizomes (those of D. composita are ranged between 3% and 4% on a dry basis, white). Substantial quantities were processed despite many more optimistic reports. As a by the Compania Agricola Industrial consequence of Marker’s work, and of con- Guatemalteca (CAIGSA). tinuing improvements in chemical technol- Ultimately, Mexico lost its preferred po- ogy, the price of progesterone to manufac- sition as a consequence of several ongoing turers of hormonal products fell from about factors. First, continued exploitation of natu- $200/g in 1940, to $80 in 1943, and to 30¢ ral stands of Dioscorea led to ever higher in 1955 (Senate Hearings, 1956). Owing to transportation costs as distances between its fortunate position with respect to the jungle and processing centers increased and geographical distribution of diosgenin-con- as second-growth stands suffered in terms of taining species, Mexico became the world yield per unit area of terrain and of assay. capital of the steroid intermediates industry, Second, other intermediates were brought a position that it held for more than 20 years. along, including stigmasterol and sitosterol A parallel, although much smaller, industry from soya oils and hecogenin from sisal

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