A missense mutation of L-gulono-gamma-lactone oxidase causes the inability of scurvy-prone osteogenic disorder rats to synthesize L-ascorbic acid.

Kawai, Tetsushi; Nishikimi, Morimitsu; Ozawa, Takayuki; Yagi, Kazuichi

doi:10.1016/s0021-9258(19)36708-0

Cited by 68 publications

(6 citation statements)

References 17 publications

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“…In this paper, we report for the first time the change in the level of ascorbate in animal tissues during vitamin C deficiency based on the newly developed specific method (Kishida et al, 1992). The used animal is a ODS rat (Mizushima et al, 1984), which cannot synthesize vitamin C by the lack of a key enzyme in ascorbate biosynthesis (Kawai et al, 1992). This animal may serve as a good model for the investigation of vitamin C deficiency, especially in relation to the role of ascorbate to prevent radical chain reactions in tissues because ascorbate has received much attention as a reducing agent since its discovery and recently it is recognized as an outstanding antioxidant (Frei et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Change in the Level of Vitamin C and Lipid Peroxidation in Tissues of the Inherently Scorbutic Rat during Ascorbate Deficiency

Tokumaru

Takeshita

Nakata

et al. 1996

J. Agric. Food Chem.

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To investigate an accurate profile of vitamin C deficiency, ascorbate deficiency was caused in the inherently scorbutic rat [Osteogenic Disorder Shionogi (ODS)], and changes in the level of the vitamin in 12 tissues of the animals (plasma, liver, stomach, small and large intestines, lung, heart, kidney, adrenal gland, spleen, muscle, and brain) were followed based on the specific method (Kishida et al. Anal. Chem. 1992, 64, 1505−1507). The level of ascorbate in plasma decreased most rapidly, and the rate of decline of the vitamin was the slowest in the brain among the 12 tissues. Based on the kinetic profile of ascorbate decay, these tissues were classified into four groups. After 25 days of ascorbate deficiency, indicators of oxidative stress changed significantly compared with the control group. The indices included increased lipid hydroperoxide level determined by the specific method (Tokumaru et al. Anal. Chim. Acta 1995, 307, 97−102) in the brain, elevated thiobarbituric acid-reactive substances (TBARS) and glutathione peroxidase activity in the heart, and the fall of glutathione in plasma and the liver. Keywords: Ascorbic acid; vitamin C; ODS rat; lipid hydroperoxide; lipid peroxidation

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Section: Introductionmentioning

confidence: 99%

Change in the Level of Vitamin C and Lipid Peroxidation in Tissues of the Inherently Scorbutic Rat during Ascorbate Deficiency

Tokumaru

Takeshita

Nakata

et al. 1996

J. Agric. Food Chem.

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“…The guinea pig has a defect in the GULO gene [ 61 ] and has been employed in numerous studies on Asc function in vivo, notably in the cardiovasular system [ 62 ]. While rats generally produce Asc, a natural mutant strain, the ODS rat, carries a missense mutatoin in the GULO gene and exhibits growth retardation with the deforming and shortening of the legs, the occurrence of mutiple fractures, oesteo porosis, and hemorrhagic tendencies [ 63 ]. However, most studies using these animals have been carried out mainly in Japan where the ODS rat was originally established.…”

Section: In Vivo Antioxidative Action Of Asc Revealed By Animal Studiesmentioning

confidence: 99%

Ascorbate Is a Primary Antioxidant in Mammals

Fujii

Osaki

2022

Molecules

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Ascorbate (vitamin C in primates) functions as a cofactor for a number of enzymatic reactions represented by prolyl hydroxylases and as an antioxidant due to its ability to donate electrons, which is mostly accomplished through non-enzymatic reaction in mammals. Ascorbate directly reacts with radical species and is converted to ascorbyl radical followed by dehydroascorbate. Ambiguities in physiological relevance of ascorbate observed during in vivo situations could be attributed in part to presence of other redox systems and the pro-oxidant properties of ascorbate. Most mammals are able to synthesize ascorbate from glucose, which is also considered to be an obstacle to verify its action. In addition to animals with natural deficiency in the ascorbate synthesis, such as guinea pigs and ODS rats, three strains of mice with genetic removal of the responsive genes (GULO, RGN, or AKR1A) for the ascorbate synthesis have been established and are being used to investigate the physiological roles of ascorbate. Studies using these mice, along with ascorbate transporter (SVCT)-deficient mice, largely support its ability in protection against oxidative insults. While combined actions of ascorbate in regulating epigenetics and antioxidation appear to effectively prevent cancer development, pharmacological doses of ascorbate and dehydroascorbate may exert tumoricidal activity through redox-dependent mechanisms.

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“…( 13 ) Among rodents, the guinea pig also carries an evolutionary defect in the Gulo gene ( 73 ) and has been utilized as a model animal for Asc function in vivo . ( 74 ) A natural mutant the Wistar rat strain, osteogenic disorder Shionogi (ODS), also carries a mutation in Gulo and develops scurvy, ( 75 ) despite it being less popular as a pathological model compared to the guinea pig. Since the mouse is the most popular laboratory animal, a huge amount of data on gene function and metabolism has accumulated.…”

Section: Animal Models With Defected Asc Synthesismentioning

confidence: 99%

Ascorbate is a multifunctional micronutrient whose synthesis is lacking in primates

Fujii

2021

J. Clin. Biochem. Nutr.

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Ascorbate (vitamin C) is an essential micronutrient in primates, and exhibits multiple physiological functions. In addition to antioxidative action, ascorbate provides reducing power to α-ketoglutarate-dependent non-heme iron dioxygenases, such as prolyl hydroxylases. Demethylation of histones and DNA with the aid of ascorbate results in the reactivation of epigenetically silenced genes. Ascorbate and its oxidized form, dehydroascorbate, have attracted interest in terms of their roles in cancer therapy. The last step in the biosynthesis of ascorbate is catalyzed by L-gulono-γ-lactone oxidase whose gene Gulo is commonly mutated in all animals that do not synthesize ascorbate. One common explanation for this deficiency is based on the increased availability of ascorbate from foods. In fact, pathways for ascorbate synthesis and the detoxification of xenobiotics by glucuronate conjugation share the metabolic processes up to UDP-glucuronate, which prompts another hypothesis, namely, that ascorbate-incompetent animals might have developed stronger detoxification systems in return for their lack of ability to produce ascorbate, which would allow them to cope with their situation. Here, we overview recent advances in ascorbate research and propose that an enhanced glucuronate conjugation reaction may have applied positive selection pressure on ascorbate-incompetent animals, thus allowing them to dominate the animal kingdom.

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A missense mutation of L-gulono-gamma-lactone oxidase causes the inability of scurvy-prone osteogenic disorder rats to synthesize L-ascorbic acid.

Cited by 68 publications

References 17 publications

Change in the Level of Vitamin C and Lipid Peroxidation in Tissues of the Inherently Scorbutic Rat during Ascorbate Deficiency

Change in the Level of Vitamin C and Lipid Peroxidation in Tissues of the Inherently Scorbutic Rat during Ascorbate Deficiency

Ascorbate Is a Primary Antioxidant in Mammals

Ascorbate is a multifunctional micronutrient whose synthesis is lacking in primates

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