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  • br History of cholesterol and bile acid research Bile


    History of cholesterol and bile phorbol research Bile is a yellow, brownish, or olive-green liquid that is composed primarily of water, organic solutes (such as lipids), inorganic salts, and some proteins. In bile, cholesterol, phospholipids, and bile acids are three major lipids, and bile pigments are minor lipids. Chemical studies of bile and gallstones for more than 200 years led to the discovery of cholesterol and bile acids, two major organic molecules in bile. The “cholesterol” was first identified in gallstones in the mid-18th century, and subsequently, this material was isolated from gallstones by some researchers. Accumulated evidence showed during the second half of the 18th century that the major component of gallstones was a white crystalline substance that is soluble in alcohol and ether, but not in water. It was not until 1816 that the compound “cholesterine” was named by chemist Michel Chevreul. After cholesterine was found to be an alcohol by Berthelot in 1859, a new name “cholesterol” was largely used in French and English scientific literature. The term cholesterol originated from the ancient Greek chole- (bile) and stereos (solid) followed by the chemical suffix -ol for an alcohol. Although cholesterol was recognized as a distinct chemical compound in the early 19th century, its chemical structure has not been known for many decades. In 1888, Reinitzer identified that the empirical formula of cholesterol was C27H46O, indicating that cholesterol was not a phorbol straight-chain compound with a double bond, since it did not have enough hydrogen atoms to bind to all the carbon valency of four. However, he saw it was consistent with a structure containing four rings with two shared carbon atoms at each ring junction (four fused rings). Subsequently, some substances isolated from fungi and green plants were found to be cholesterol-like crystalline compounds. In 1889, Tanret isolated a substance from rye seeds infected with ergot, which closely resembled cholesterol. This compound was named ergostérine (now called ergosterol). Furthermore, the empirical formulae of cholic acid (C24H40O5), which was found by Strecker in 1848, and of deoxycholic acid (C24H40O4), which was found by Mylius in 1886, displayed a highly similar ratio (1.67) of hydrogen to carbon atoms compared with that (1.70) in cholesterol. Because both bile acids and cholesterol are present in bile, it was reasonable to hypothesize that the structural features of these two compounds could be similar. In 1919, Windaus and his colleagues found that the carbon skeleton of bile acids was the same as that of the cholesterol molecule, for the most part. This discovery greatly promoted the study of the chemical structure of cholesterol because the presence of the hydroxyl group in ring C of cholic and deoxycholic acids enabled Windaus and other researchers to further investigate the steroid ring system through the bile acid approach. In 1928, the Nobel Committee for Chemistry announced that the Nobel Prize in Chemistry 1927 was awarded to Heinrich Wieland “for his investigations of the constitution of the bile acids and related substances,” as well as that the Nobel Prize in Chemistry 1928 was given to Adolf Windaus “for the services rendered through his research into the constitution of the sterols and their connection with the vitamins.” Thus, on December 10, 1928, two Nobel Prizes in Chemistry were awarded to Wieland and Windaus, respectively. In his Nobel lecture, Wieland first described a brief history of how three bile acids (including cholic, deoxycholic, and lithocholic acids) were discovered and then, summarized his chemical experiments of bile acids. Based on his experimental results, he proposed a possible chemical structure of bile acid. In his Nobel lecture, Windaus presented his discovery that the chemical precursor of vitamin D was a member of the sterol group and also showed how sunlight broke one of the chemical bonds in the parent molecule, converting it into the active vitamin. This finding clearly explained why exposure to sunlight could prevent rickets, a disease caused by vitamin D deficiency in humans. In addition, Windaus proposed a possible chemical structure of cholesterol. He spent some 30 years studying the chemical structure of cholesterol, which was part of his study of the complex alcohols, known as sterols. He found that sterols were closely related to bile acids by transforming cholesterol into cholanic acid. Unfortunately, the steroid nucleus of bile acid and cholesterol shown in their Nobel lectures was incorrect. However, this did not significantly influence their excellent findings and conclusions for which their prizes were awarded.