Perspectives in Biology and Medicine

FOUC ACID: DISCOVERY AND THE EXCITING FIRST DECADE ARNOLD D. WELCH* Several detailed reviews ofthe subject covered in this article have been presented; of these, four of the earliest were those of Snell and Wright [1], Welch and Heinle [2], Jukes and Stokstad [3], and Welch and Nichol [4]· Studies in 1941 and 1942 (Black, McKibbin, and Elvehjem [5]; Black, Overman, Elvehjem, and Link [6]; Welch [7]; Welch, Mattis, and Latven [8]; Welch and Wright [9]; Daft, Ashburn, and Sebrell [10]) ofthe effects on growing rats of highly purified diets containing sulfonamides (used to inhibit the potential synthesis of nutritionally important factors by intestinal microorganisms) had suggested the involvement of a hitherto unrecognized vitamin. Thus, there was disclosed the need for an essential substance, which, it appeared reasonable to suggest, might be formed from para-aminobenzoic acid by certain intestinal microorganisms . Accordingly, in the absence of a dietary source of the factor, the animals became dependent on the sulfonamide-sensitive bacteria for a supply of a substance they could not themselves synthesize. This growth factor probably was the same as that referred to earlier as the Wills factor or vitamin M (for monkeys) [2]; however, the work in the early 1940s led to the introduction of such terms as the L. casei (from Lactobacillus casei) factor, vitamin Bc (for chicks), and folic acid. The name "folic acid," which eventually came into wide usage, was introduced by 1941 by Mitchell, Snell, and Williams [11] because of the demonstrated occurrence of this substance (or class of substances) in certain leafy vegetables, for example, spinach, although liver and various other biological materials were also sources of the factor(s). Especially This article is based on an invited paper on "Early Laboratory Studies on Xanthopterin, Folic Acid, and Its Antagonists, including Aminopterin," which was presented at a Symposium of the Federated Societies of Biology and Medicine, Atlanta, Georgia, April 1981 ; it concentrates on the decade 1941-1951. * Drug Evaluation Branch, DCT National Cancer Institute, NIH, Blair Building, 9000 Rockville Pike, Bethesda, Maryland 20205.© 1983 by The University of Chicago. All rights reserved. 0031-5982/84/2701-0374$01.00 64 I ArnoldD. Wekh ¦ FolicAcid useful for detection and assays of this type of material were microorganisms that could not synthesize folic acid (or functionally related compounds). Such bacterial species as L. casei e (ATCC 7469) and Streptococcus lactis R (also termed S.faecalL·, now designated as S.faecium [ATCC 8043]) were then widely employed. In addition to the likely relationship between folic acid and paraaminobenzoic acid, studies by Welch and co-workers [12-14] implied that the compound also might be related to xanthopterin, a member ofa class of substances previously found in nature, for example, in human urine, as well as in the wings ofcertain yellow butterflies. (The collection of such butterflies is said to have been stopped by Reichsführer Hitler because of the lethal cruelty to these insects.) These studies with xanthopterin showed that the apparent content of "folate" in the liver of rats could be increased several-fold by incubation of slices of this tissue with this pterin (but not by a closely related compound, leucopterin) (fig. 1). At first, it was not clear whether xanthopterin, which then was not available in an isotopically labeled form, served either as a precursor of a compound with the microbial activity offolic acid or possibly inhibited the metabolic inactivation ofthe L. casei factor in incubating liver. Only in 1951 were studies described by Heinle, Welch, and co-workers [2, 4, 15], in which [6,7-14C]xanthopterin was used; these demonstrated that the pterin actually did not serve as a precursor of folic acid either in vitro or in vivo. Accordingly, it appeared that the pterin probably inhibited the metabolic inactivation of the L. casei factor. Another development of interest involved the finding that, although powdered cow's milk contains essentially no microbially detectable substances of the folic acid-type [16], this material protected rats (given purified diets containing succinylsulfathiazole) against the multiple manifestations of folate deficiency [12-14, 17, 18]. These signs of deficiency included, especially, depression of growth, low levels of the L. casei factor in the liver, and a decreased...