VITAMINS

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Vitamin D(D) exerts a wide variety of biological actions such as calcium homeostasis, celluar differentiation and proliferation. Most of these actions are thought to be mediated through D receptor-mediated gene expression. Vitamin D receptor(VDR) is a member of steroid/thyroid hormone, vitamin A, nuclear receptor superfamily, and acts as a ligand-inducible transcription factor. The transactivation function of VDR is activated by binding of a hormonal form of D, 1,25-(OH)_2D_3. Our preliminary study of vitamin A deficient animals suggested that an ultimate model for D deficiency remains to be established. Therefore, to know the role of 1,25(OH)_2D_3-VDR axis in the D actions in intact animals, we have generated VDR deficient mice by gene targeting. The heterozygous and homozygous(null) VDR mutant mice gave a birth, grew normaly until weaning, and displayed no abnormality. However, only the VDR null mice showed growth retardation after weaning, and became rickets with alopecia, similar to human type II rickets, reaching a death at around 15 weeks. Detailed analysis revealed that impaired bone formation is due to impaired mineralization, but the numbers of osteoblasts and osteoclasts are apparently normal. Along with this finding, the in vitro co-culture system confirmed the significant, but not essential, role of D in the cytodifferentiation of osteoclasts. Consistent with infertility, uterine hypoplasia was found, but such abnormality could not be detected in the male reproductive organs. Thus, the present study established in vivo role of VDR in intact animals.

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Vitamin K(K) is prophylactically administered to neonates to prevent hemorrhagic diseases of the newborn. Some recent reports suggest that the risk of childhood cancer significantly increased with the intramuscular injection of K. K is cyclically metabolized to K-epoxide in the liver microsomes, and K-epoxide reductase catalyzes the conversion of K-epoxide to K again. It is inferred that the epoxide group is likely to injure the DNA and becomes carcinogenic by releasing superoxide. The object of this study is to estimate the K_1-epoxide appearance in neonatal plasma after intramuscular injection of K_1 (1 mg) and compare with the control group. In the control group (n=9) between 2.8 and 93.1 hours of age, the mean concentration of K_1 was 2.7 ng/ml (range 0.6〜5.8) and K_1-epoxide was not detectable (<0.5 ng/ml) in any sample. In the administered group (n=17) between 5.7 and 93.8 hours of age, the mean concentration of K_1 was 246.2 ng/ml (range 6.4〜717.9) and significantly higher (p<0.005) than the control, and the mean concentration of K_1-epoxide was 3.5 ng/ml (range n.d.〜8.0). In the control group, short transit and very low concentration of K-epoxide have little toxic damage on infants. However, the long time exposure to higher levels of K-epoxide in plasma may increase the risk of childhood cancer by release of superoxide, although it is uncertain whether the maximum K_1-epoxide concentration (8.0 ng/ml) in this study may have adverse effects on his health or not.

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Water-immersion restraint stress is known to induce gastric ulcer in rats by oxidative stress via free radicals. Protective effects of natural β-carotene were examined in rats, which were fed a diet containg 0.05% natural β-carotene for 2 weeks, against water-immersion stress ulcer. 1. Ulcer index and ulcer area estimated by morphometrical analysis were inhibited to 50% in rats fed a natural β-carotene diet as comparison with those fed a standard diet. 2. Plasma concentration of β-carotene and ratio of 9cis/trans β-carotene decreased remarkably after water immersion stress. These results suggest that antioxidant effects of natural β-carotene suppress the development of stress ulcer induced by water-immersion restraint. Natural β-carotene is effective in protecting the stress ulcer.

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