Search

Retinol and its derivative, retinoic acid, have pleiotropic functions including vision, immunity, hematopoiesis, reproduction, cell differentiation/growth, and development. Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases in developed countries and encompasses a broad spectrum of forms, ranging from steatosis to steatohepatitis, which develops further to cirrhosis. Retinol status has an important role in liver homeostasis. The purpose of this study was to evaluate the retinol status and expression of retinol-related proteins, including enzymes and binding proteins, in methionine-choline deficient (MCD) rats as a model of NAFLD. We examined retinol levels in the plasma and liver and gene expression for β-carotene 15,15'-monooxygenase (BCMO), lecithIn: retinol acyltransferase (LRAT), aldehyde dehydrogenase 1A1 (ALDH1A1), ALDH1A2, and cellular retinol binding protein (CRBP)-I in MCD rats. The plasma retinol levels in MCD rats were lower than those in the controls, whereas hepatic retinol levels in MCD rats were higher. BCMO expression in the intestine and liver in MCD rats was lower, whereas that in the testes and the kidneys was higher than in control rats. Expression of LRAT, CRBP-I, ALDH1A1, and ALDH1A2 in the liver of MCD rats was also higher. Altered expression of retinol-related proteins may affect retinol status in NAFLD.

Vitamin E plays a critical role as an antioxidant in several pathological conditions, including diabetes, cancer, cardiovascular diseases, and neurodegenerative disorders. Diabetes is a metabolic disorder of glucose due to the lack of adequate insulin production (type 1) or peripheral insulin resistance (type 2). Oxidative stress plays a major role in the pathogenesis of diabetes and its complications. The purpose of the present study was to determine α-tocopherol status and the expression of α-tocopherol-related proteins, including binding proteins and metabolizing enzymes, under streptozotocin (STZ)-induced type 1 diabetes in rat models. In STZ rats, plasma α-tocopherol levels decreased compared to the control rats, whereas hepatic α-tocopherol levels in the STZ rats were significantly increased. CuZn-superoxide dismutase (SOD) gene expression in the liver of STZ rats was markedly decreased, whereas Mn-SOD gene expression remained unaltered. Accelerated lipid peroxidation in the liver of STZ rats was observed and the hepatic expression of α-tocopherol transfer protein (α-TTP) in STZ rats decreased compared to that in the controls. The hepatic expression of cytochrome P450 4F2 (CYP4F2) and CYP3A2 genes in STZ rats also decreased. The reduced expression of hepatic α-TTP and CYP4F2 genes probably leads to decreased plasma α-tocopherol levels and elevated α-tocopherol levels in the liver of STZ rats. The altered expression of hepatic α-tocopherol-related proteins might regulate α-tocopherol status in type 1 diabetes. Determining the mechanism of modulating α-tocopherol status may be helpful in promoting antioxidant therapy in diabetes.

Vitamin E, a critical fat-soluble vitamin antioxidant, is expressed on cell membranes and prevents propagation of lipid peroxidation. α-Tocopherol transfer protein (α-TTP) is a cytosolic protein located in the hepatocytes that acts as the principal regulator of the circulating α-tocopherol levels. Type 2 diabetes is a metabolic disorder characterized by hyperglycemia, caused by insulin resistance. Lipid peroxidation promotes the clinical progression and development of complications in type 2 diabetes. Results of animal and human experiments on the vitamin E status in diabetes are conflicting. The present study was conducted with the objective of investigating the vitamin E status and α-TTP expression in Goto-Kakizaki (GK) rats, a model of type 2 diabetes. In diabetic GK rats, increases of the α-tocopherol levels in the plasma and liver were observed as compared with the levels in the controls. No alternation in the CuZn-superoxide dismutase (SOD) or Mn-SOD gene expression was found in the liver of GK rats as compared with that in the controls. The GK rats showed an increase of the hepatic expression of the α-TTP gene as compared with the level in the controls. It can be suggested that the increased hepatic α-TTP gene expression levels may influence plasma α-tocopherol levels in the diabetic animals. Hence, investigation of the regulatory factors of α-TTP expression may provide important clues to highlighting the antioxidant mechanisms of vitamin E.

Recently, there has been an increasing concern about noncommunicable diseases (NCDs), in which oxidative damage plays a role. In this paper, we have re-analyzed the data from the National Health and Nutrition Survey (NHNS) 2007 to study the relationship between an NCD (e.g. hypertension) and the dietary intake of vitamin E, a potent anti-oxidative vitamin. The inclusion criteria were those aged 40 and over, excluding pregnant or lactating women, and data from 1,405 males and 2,102 females were analyzed. The mean ages were 63.5 and 62.4, respectively. Nutrients intake was evaluated from a semi-weighted, 1-d household dietary record. When the subjects were categorized into tertiles based on their vitamin E intake, higher vitamin E intake was associated with a lower percentage of subjects with hypertension (p for trend=0.01). Subjects with higher vitamin E intake had higher energy intake-adjusted intake of other nutrients which have been considered to be related to hypertension such as potassium, magnesium, and vitamin C. Logistic regression analysis was done with the low tertile of vitamin E intake as the reference. The medium and high tertiles of vitamin E intake were associated with a significantly lower odds ratio for hypertension, 0.73 (95% CI; 0.62-0.87) for the former and 0.81 (95% CI; 0.69-0.96) for the latter. Additional analyses, one adjusted for the indices associated with hypertension and one excluding the subjects with vitamin E supplementation, have yielded the similar results. In summary, re-analysis of data from NHNS has revealed that higher vitamin E intake was significantly associated with lower prevalence of hypertension.

We administered high-dose vitamin E to healthy adult male volunteers and assessed the safety of such supplementation. Fourteen volunteers received daily 1,200 IU of vitamin E (800 mg of D-alpha-tocopherol) for 28 d and eight controls were also enrolled. The volunteers treated with vitamin E showed no abnormalities during the study period. The alpha-tocopherol concentrations of plasma and platelets were markedly elevated by vitamin E treatment, but there were no significant differences in platelet aggregation, coagulation, and the clinical parameters between the two groups. In conclusion, a high dose of vitamin E for 28 d had no adverse effects in healthy men.

All-trans retinoic acid (ATRA) is used as differentiation therapy for acute promyelocytic leukemia (APL). The two major adverse effects of ATRA therapy are hyperleukocytosis and retinoic acid syndrome. In order to prevent these adverse effects, low-dose ATRA therapy (25 mg/m 2 /d) has been tried in adults. Accordingly we assessed the pharmacokinetics of low-dose ATRA in children with cancer. Four children (one with APL and three with other advanced cancer) were administered ATRA and its pharmacokinetics were evaluated. In three patients, the pharmacokinetic parameters of ATRA were similar to those previously determined for APL patients in remission, but the values were lower in one patient. Low-dose ATRA was effective for APL, but not for the solid tumors. This therapy did not cause any severe toxicity. Further studies are needed to determine the optimum ATRA regimen and to evaluate low-dose ATRA combined with chemotherapy in children with APL.

In neonatal medicine, it is thought that retinol is useful for preventing CLD and for fetal development. However, beta-carotene had other vitamin A precursors have not been studied in neonates with CLD or others disorders. Cord blood of neonates including ELBW and VLBW infants was assayed for plasma levels of retinol, RBP, beta-carotene and cryptoxanthin. Plasma beta-carotene levels in ELBW and VLBW were lower than that in term infants, but plasma cryptoxanthin levels in ELBW and VLBW were about the same as in term infants. Plasma retinol and RBP levels showed almost same levels during 23-41 gestational weeks. Maternal smoking reduced plasma beta-carotene but not cryptoxanthin, retinol, or RBP levels. IUGR was associated with increased cryptoxanthin levels in cord blood. Serious neonatal diseases, including CLD and ROP manifested no significant effects on the cord blood vitamin levels. Thus, the occurrence of these diseases at birth could not be predicted by examination of vitamin levels in cord blood.

Retinol and its active derivative retinoic acid have an important role in development, reproduction, immunity, and cell proliferation/differentiation. Obesity and dyslipidemia are risk factors for cardiovascular disease that may affect hepatic homeostasis. It is unclear whether the expression of retinol-related proteins is affected and influences the retinol status in obesity and dyslipidemia. The aim of this study was to evaluate the retinol status and expression of retinol-metabolizing enzymes and binding protein in obese and dyslipidemic fa/fa (Zucker) rats. We examined the expression of genes for β-carotene 15,15' monooxygenase (BCM), lecithin:retinol acyltransferase (LRAT), cellular retinol binding protein-I (CRBP-I), and cytochrome P450 26A1 (CYP26A1) in fa/fa rats and lean control rats. We also measured the retinol level in plasma and liver samples from both groups. Plasma retinol levels in fa/fa rats were increased compared with lean rats, while hepatic retinol levels were similar in both groups. In obese and dyslipidemic fa/fa rats, intestinal BCM gene expression was increased, whereas hepatic LRAT gene expression was deceased. There was no difference in hepatic CRBP-I and CYP26A1 gene expression between fa/fa rats and lean rats. Altered expression of BCM and LRAT genes may affect plasma retinol status in obesity and dyslipidemia.

We examined the distribution of beta-carotene in plasma lipoprotein fractions. In healthy children and adults, LDL contained more beta-carotene than did HDL, but in cord blood more beta-carotene was found in HDL than in LDL. After the oral administration of beta-carotene, its plasma level rose although its distribution in the individual lipoprotein fractions did not change. Among disease conditions associated with hyperlipidemia, the ratio of beta-carotene to plasma lipids was highest in anorexia nervosa, while nephrotic syndrome and diabetes mellitus had similar ratios to each other.

Using a hypoxanthine-xanthine oxidase (HX-XOD) reaction system, the effect of vitamin E (VE) on oxidative membrane injury was studied by the impedance method. Both VE-sufficient and VE-deficient erythrocytes showed an elevation of low frequency permittivity in the early phase of reaction. In the later phase of reaction, VE-sufficient erythrocytes showed a sustained elevation in permittivity, while VE-deficient erythrocytes showed a decrease in permittivity with time. These changes consisted with the process of hemolysis in the HX-XOD system. The similarity of early phase change between VE-sufficient and VE-deficient erythrocytes indicates that the HX-XOD system exerted a similar effect on both erythrocytes in the early phase. The difference in changes of later phase between the two types of erythrocytes suggests that VE suppressed the reduction in permittivity. When the results were analyzed by the Pauly-Schwan's theory based on the assumption that erythrocytes are spherical, the product of VE-deficient or VE-sufficient erythrocyte size (R) and membrane capacity (Cm) showed a change similar to that in permittivity.

1. Tocopherol concentrations in plasma, red blood cells (RBCs), and buccal mucosal cells were examined in newborn infants (before feeding), children (2-15 years old), and adults. Tocopherol concentrations in adults and newborn infants showed the greatest difference in plasma and the smallest difference in RBC. Buccal cell tocopherol concentrations in adults were 2.3 times higher than those in infants. The majority of newborn infants had RBC tocopherol levels below the normal limit (115 micrograms/100 ml of packed cells). Also, more than one third of buccal cell tocopherol levels determined in newborn infants were below a level of 15 ng/mg protein, which was determined as the lower limit of normal in healthy children on the basis of the testing of 97 samples. 2. After administration of a daily dose of 600 mg of RRR-alpha-tocopherol for three months to young adults, tocopherol levels in buccal mucosal cells reached a level of more than 4 times the basal level after rising throughout the 3-month period, while levels in RBC and plasma showed less than a 3-fold increase and reached a maximum within one month. Buccal cell tocopherol levels showed a poor correlation to the RBC and plasma tocopherol levels, while the tocopherol/lipid ratio was closely correlated with RBC and plasma tocopherol levels. After a single dose of 600 mg of RRR-alpha-tocopherol, RBC and plasma tocopherol concentrations reached a maximum within 24 hours, while buccal cell tocopherol did so 4 to 6 days later. 3. Very obese children and hyperlipemic obese children showed lower buccal cell tocopherol levels, accompanied by lower RBC tocopherol levels and higher plasma tocopherol levels, when compared with non-obese children and normolipemic obese children.

1. Vitamin E content in the adipose tissue was examined in rats with and without vitamin E deficiency. With the progression of vitamin E depletion, the more rapid decrease in tocopherol concentration was observed in brown adipose tissue (BAT) than in white adipose tissue (WAT), and the rate of decrease of tocopherol was approximately three times faster in BAT than in WAT. After the intramuscular administration of 10 mg/kg of all-rac-tocopheryl acetate twice a week for two weeks to vitamin E-deficient rats, a similar pattern of increase was observed in the tocopherol concentrations of BAT and WAT, although the rate of increase was slower in WAT than in BAT. 2. Changes of tocopherol concentration in BAT and WAT were investigated in normo-nourished rats with hyperlipemia produced by the intramuscular injection of Triton WR-1339 for 7 days. A marked increase in tocopherol concentration was observed in both BAT and WAT in the late period of hyperlipemia, with the increase being greater in WAT. 3. The fatty acid composition of adipose tissue was compared between rats with and without vitamin E deficiency. No significant differences were observed in BAT and WAT between the two groups. 4. The glucose uptake of WAT was not altered in vitamin E-deficient rats when compared with control rats.

We investigated the vitamin A status and beta-carotene 15,15'-dioxygenase activity in hairless mice with UV exposure to assess the regulation of vitamin A metabolism after UV irradiation. HR-1 hairless mice were irradiated with UV at 3 J/cm2 for 5 d. After UV irradiation, the mice were sacrificed and samples were obtained to analyze the retinoid concentration, expression of RXR-alpha, and beta-carotene 15,15'-dioxygenase activity. After UV exposure, the skin retinoid concentration was significantly lower as well as the expression of RXR-alpha. Higher skin beta-carotene dioxygenase activity was observed in the UV group as compared to the control group. We found no significant differences in the alpha-tocopherol concentration or acrolein levels in the skins of the two groups. In conclusion, the elevation of beta-carotene 15,15'-dioxygenase activity in hairless mice after UV exposure may be a response to reduction of the skin retinoid concentration.

We measured retinol levels and beta-carotene 15,15'-dioxygenase activity in rats with streptozotocin-induced diabetes mellitus to assess the relationship between the disease and the conversion of beta-carotene to retinol. The plasma retinol level was significantly lower in diabetic rats than in control rats, but the hepatic retinol level was significantly higher than the control. The hepatic dioxygenase activity, but not that of the intestinal mucosa, was significantly lower in diabetic rats than in control rats. The hepatic dioxygenase activity showed a significant negative correlation with the hepatic retinol levels. The results suggest the disturbed secretion of retinol from the liver and suppression of hepatic dioxygenase activity by the retinol increased in the liver in diabetic rats.

Plasma beta-carotene, alpha-tocopherol and retinol were measured in 15 female and 5 male children with insulin-dependent diabetes mellitus (IDDM), and the correlations with plasma hemoglobin A1c (HbA1c) and fructosamine were analyzed. Twelve female and 8 male children served as age-matched controls. The plasma beta-carotene and alpha-tocopherol levels of the IDDM children were significantly higher than those of the control children, but there were no differences in plasma retinol or total lipid levels. The plasma beta-carotene level, beta-carotene/retinol ratio and beta-carotene/total lipids ratio each showed significant correlations with serum HbA1c and fructosamine in all subjects studied. Similarly, the plasma alpha-tocopherol level and alpha-tocopherol/total lipids ratio were correlated with these indexes of glycemic control. These findings suggest certain mechanisms may exist to prevent lipid peroxidation and vascular complications in IDDM patients.

Developmental changes in expression of alpha-tocopherol transfer protein (alpha-TTP) after birth were investigated using rats with respect to plasma changes of tocopherols. The expression of alpha-TTP in the neonatal rat liver, which was very low immediately after birth, increased steadily during the two weeks of life before weanling and reached the adult level at four weeks. During the suckling period, the plasma ratio of alpha-tocopherol to gamma-tocopherol linearly increased, because plasma alpha-tocopherol which was low immediately after birth, increased rapidly during the period, while gamma-tocopherol remained unchanged. The increase in the ratio seemed to correlate with the developmental expression of alpha-TTP in the liver during this period. The ratio also reached the adult level after four weeks. The expression of alpha-TTP was investigated using primary cultured rat hepatocytes. The expression of alpha-TTP was found to be extremely low after 20h of culture. The decrease in alpha-TTP expression was exacerbated by adding epidermal growth factor to the culture medium and was inhibited by adding dexamethasone. These observations suggest that expression of alpha-TTP may be affected by the state of hepatic differentiation.

Therapy with all-trans retinoic acid (ATRA) achieves complete remission in a high proportion of patients with acute promyelocytic leukemia (APL), but the efficacy is reported to relate to plasma ATRA level after oral administration. The pharmacokinetics of ATRA and 4-oxo all-trans retinoic acid (4-oxo ATRA), a metabolite of ATRA, were studied in four children with APL at the time of initial oral administration. After administration of ATRA at a dose of 30 mg/m2, the peak plasma ATRA level was 20-741 ng/ml and was reached at 60-120 min. The patient with the lowest peak plasma level did not achieve complete remission and had a very high 4-oxo ATRA level compared to the patients with complete remission. These findings suggest that accelerated metabolism of ATRA plays a role in the failure of this agent in the patients without remission.

The nutritional status with respect to vitamins A and E, and beta-carotene was examined in elderly Japanese subjects in two institutions at Osaka and Kyoto. Only the plasma vitamin E level has been determined in the majority of previous investigations. In this study, vitamin E levels were determined in red blood cells (RBCs), platelets (PLT), mononuclear cells (MN), polymorphonuclear cells (PMN), and buccal mucosal cells (BMC), using HPLC with electrochemical detection. Alpha-tocopherol levels in plasma and RBCs did not differ between elderly and young adults, while those in PLT, MN, and BMC were lower in the elderly. Thus, the vitamin E status of elderly Japanese individuals appears to be inadequate of the cellular levels. The daily vitamin E intake of the elderly subjects was below the recommended dietary allowance for the Japanese population. Plasma levels of retinol and beta-carotene were also assessed. The vitamin A status did not differ between elderly and young adults on the basis of the levels of retinol and retinol-binding protein (RBP). The daily intake of retinol (as retinol equivalent) by the elderly subjects was more than 2,000 IU. With respect to beta-carotene, there was a large sex difference (female > male), which was more prominent in the young adults and became smaller in the elderly. This sex difference was partly attributable to a difference in plasma total lipids. No clear age-related trend was noted.

Erythrocytes of vitamin E-deficient rats and normal rats were oxidized at 37 degrees C by molecular oxygen using a free radical initiator. The erythrocytes were oxidized by a free radical chain mechanism with kinetic chain length considerably larger than 1 and resulted in hemolysis. Vitamin E suppressed both oxidation and hemolysis, but the extent of hemolysis was determined primarily by the extent of oxidation independent of the presence or absence of vitamin E.

Red blood cell (RBC) alpha-tocopherol and fatty acid levels in children undergoing long-term antiepileptic therapy were examined. Antiepileptic drugs included diphenylhydantoin (PHT), valproic acid (VPA), phenobarbital (PB), and carbamazepine (CBZ). RBC alpha-tocopherol levels were low in patients receiving multi-drug combination therapy, as compared with children receiving no treatment (controls), but plasma alpha-tocopherol levels were the same in both groups. With respect to fatty acid composition in RBCs, docosahexaenoic acid (DHA) level was decreased in children receiving antiepileptic therapy, while no changes were documented in the other fatty acids.