1 How Dietary Deficiency Studies Have Illuminated the Many Roles …
9
Development of the Field
Vitamin A acid was first tested biologically by Arens and Van Dorp (ref cited within), who
isolated crystalline vitamin A acid as an intermediate in their synthesis of vitamin A. On
feeding vitamin A acid to deficient rats, they found that the animals promptly began to grow
again and were relieved of their deficiency symptoms (Dowling 1961).
Search for a Mechanism of Action
The results of many studies carried out in the early 1900s using a vitamin A deficiency experimental model indicated that vitamin A (1) was all-trans-retinol; (2)
was required for reproduction, embryonic development, and continued health and
well-being during postnatal life; and (3) was obtained by consuming plants that produce vitamin A precursors or animal organs that store retinol. Studies showed that a
derivative of vitamin A, vitamin A acid, with chemical name all-trans-retinoic acid,
imparted many of the same effects as retinol. Further work carried out in many laboratories revealed that retinoic acid can be generated from vitamin A through a two-step
process catalyzed by retinol dehydrogenase (RDH) and retinaldehyde dehydrogenase (RALDH) (Fig. 1.1B). The acid form of the vitamin does not cure the blindness
that accompanies severe vitamin A deficiency. In this case, lack of retinol leads to a
deficiency of 11-cis-retinaldehyde, the chromophore that unites with opsin to form
the visual pigment, rhodopsin.
During the second half of the twentieth century, an important goal for vitamin A
researchers was determining the mechanism for effects of retinol and/or retinoic acid
on growth related processes. Until the tools of molecular biology were developed in
the 1980s, researchers continued to use a vitamin A deficiency experimental model to
attempt to answer this question see for example, (Lamming et al. 1954; Klein-Szanto
et al. 1980; Bang et al. 1972; Havivi and Tal 1974; Rindi et al. 1970; Jayaram et al.
1975; Krause et al. 1975; Johnson et al. 1969; Omori and Chytil 1982).
Several groups focused their efforts on determining whether vitamin A deficiency
changed normal RNA or protein metabolism hypothesizing that retinol was somehow
involved in transcription or translation processes. As examples, Zachman and Zile
and DeLuca reported that administering retinol intravenously to vitamin A deficient
rats induced RNA synthesis in the colon, intestine, and liver (Zachman 1967; Zile
and DeLuca 1970), and Deluca, Little, and Wolf found that vitamin A deficiency
led to a decrease in protein translation in the endoplasmic reticulum of intestinal
mucosal cells (DeLuca et al. 1969).
By 1979, a cellular retinol binding protein (CRBP) and a cellular retinoic acid
binding protein (CRABP) had been discovered (Napoli 2016). Takase and coworkers
observed that CRBP enabled retinol to bind to nuclei isolated from the livers of
vitamin A deficient rats. In their report of this finding, the Chytil lab proposed a
mechanism of vitamin A action. They posited that (1) a specific intracellular protein
9
Development of the Field
Vitamin A acid was first tested biologically by Arens and Van Dorp (ref cited within), who
isolated crystalline vitamin A acid as an intermediate in their synthesis of vitamin A. On
feeding vitamin A acid to deficient rats, they found that the animals promptly began to grow
again and were relieved of their deficiency symptoms (Dowling 1961).
Search for a Mechanism of Action
The results of many studies carried out in the early 1900s using a vitamin A deficiency experimental model indicated that vitamin A (1) was all-trans-retinol; (2)
was required for reproduction, embryonic development, and continued health and
well-being during postnatal life; and (3) was obtained by consuming plants that produce vitamin A precursors or animal organs that store retinol. Studies showed that a
derivative of vitamin A, vitamin A acid, with chemical name all-trans-retinoic acid,
imparted many of the same effects as retinol. Further work carried out in many laboratories revealed that retinoic acid can be generated from vitamin A through a two-step
process catalyzed by retinol dehydrogenase (RDH) and retinaldehyde dehydrogenase (RALDH) (Fig. 1.1B). The acid form of the vitamin does not cure the blindness
that accompanies severe vitamin A deficiency. In this case, lack of retinol leads to a
deficiency of 11-cis-retinaldehyde, the chromophore that unites with opsin to form
the visual pigment, rhodopsin.
During the second half of the twentieth century, an important goal for vitamin A
researchers was determining the mechanism for effects of retinol and/or retinoic acid
on growth related processes. Until the tools of molecular biology were developed in
the 1980s, researchers continued to use a vitamin A deficiency experimental model to
attempt to answer this question see for example, (Lamming et al. 1954; Klein-Szanto
et al. 1980; Bang et al. 1972; Havivi and Tal 1974; Rindi et al. 1970; Jayaram et al.
1975; Krause et al. 1975; Johnson et al. 1969; Omori and Chytil 1982).
Several groups focused their efforts on determining whether vitamin A deficiency
changed normal RNA or protein metabolism hypothesizing that retinol was somehow
involved in transcription or translation processes. As examples, Zachman and Zile
and DeLuca reported that administering retinol intravenously to vitamin A deficient
rats induced RNA synthesis in the colon, intestine, and liver (Zachman 1967; Zile
and DeLuca 1970), and Deluca, Little, and Wolf found that vitamin A deficiency
led to a decrease in protein translation in the endoplasmic reticulum of intestinal
mucosal cells (DeLuca et al. 1969).
By 1979, a cellular retinol binding protein (CRBP) and a cellular retinoic acid
binding protein (CRABP) had been discovered (Napoli 2016). Takase and coworkers
observed that CRBP enabled retinol to bind to nuclei isolated from the livers of
vitamin A deficient rats. In their report of this finding, the Chytil lab proposed a
mechanism of vitamin A action. They posited that (1) a specific intracellular protein