Vitamin A 

Yang, L. M., U. C. Tin, et al. (1999). "Role of retinoid receptors in the prevention and treatment of breast cancer." J Mammary Gland Biol Neoplasia 4(4): 377-88.

Retinoids are vitamin A-related compounds that have been found to prevent cancer in animals and humans. In this review, we discuss the role of retinoids and their receptors in the treatment and prevention of breast cancer. The retinoid receptors are expressed in normal and malignant breast cells, and are critical for normal development. In breast cells, when bound by retinoid hormones, these proteins regulate proliferation, apoptosis, and differentiation. The mechanism by which retinoids inhibit breast cell growth has not been completely elucidated, however, retinoids have been shown to affect multiple signal transduction pathways, including IGF-, TGFbeta-, and AP-1- dependent pathways. Retinoids have also been shown to suppress the growth and prevent the development of breast cancer in animals. These agents suppress tumorigenesis in carcinogen-treated rats and in transgenic mice, and inhibit the growth of transplanted breast tumors. These promising preclinical results have provided the rationale to test retinoids in clinical trials for the treatment and prevention of breast cancer. Several retinoids, including all trans retinoic acid and 9-cis retinoic acid, have been shown to have modest activity in the treatment of breast cancer, and these agents are now in clinical trials in combination with cytotoxic agents and anti-estrogens. Another retinoid, 4-HPR, is currently being tested in a human cancer prevention trial. Preliminary results suggest that 4-HPR may suppress breast cancer development in premenopausal women. Future clinical trials will focus on testing new synthetic retinoids that have reduced toxicity and enhanced therapeutic and preventive efficacy.

Buss, N. E., E. A. Tembe, et al. (1994). "The teratogenic metabolites of vitamin A in women following supplements and liver." Hum Exp Toxicol 13(1): 33-43.

Ten healthy female volunteers were given 5 doses of retinol as the palmitate; 50 and 150 mg retinol as an oral supplement, 50 and 150 mg as fried calf liver (50 and 150 g) and 3, 9 or 30 mg by intra-muscular injection. Plasma concentrations of retinyl palmitate were higher after 50 mg retinol given as an oral supplement compared with 50 mg as liver; there was no significant difference between the 150 mg doses. Plasma concentrations of retinol showed only small increases. The peak plasma concentrations (Cmax) of all-transretinoic acid, the principal teratogenic metabolite of retinol, and the area under the concentration- time curve (AUC) were up to 20-times higher after supplements compared to the same dose as liver. Plasma concentrations of all-trans-4-oxo- retinoic acid, 13-cis-retinoic acid and 13-cis-4-oxo-retinoic acid showed smaller differences between supplements and liver. Intra- muscular administration of 30 mg retinol gave retinyl palmitate concentrations similar to those found after the oral doses but did not increase circulating concentrations of the acid metabolites. Based on the formation of all-trans-retinoic acid, liver and supplements are not of equivalent teratogenic potential. Advice to pregnant women on the consumption of liver based on the reported teratogenicity of vitamin A supplements should be reconsidered.

Spear, P. A. and T. W. Moon (1986). "Thyroid-vitamin A interactions in chicks exposed to 3,4,3',4'- tetrachlorobiphenyl: influence of low dietary vitamin A and iodine." Environ Res 40(1): 188-98.

Poultry chicks receiving a low vitamin A semipurified diet and exposed to 3,4,3',4'-tetrachlorobiphenyl became hypothyroid in comparison with unexposed controls. Metabolic rate, total serum thyroxine, total serum triiodothyronine, and food intake decreased significantly while thyroid weight increased. Unexpectedly, growth rate was not affected on this diet. In the case of chicks receiving a low vitamin A--low iodine semipurified diet and exposed to the PCB congener, the hypothyroid response was apparently antagonized. Comparing exposed chicks with unexposed controls, metabolic rate and the proportion of free T3 (i.e., %T3 resin uptake) increased while total serum thyroxine and thyroid weight were unchanged. In addition, growth rate, food consumption, and serum retinol decreased on this diet. These results are interpreted to mean that growth rate may have been altered by circulating levels of retinol, and vitamin A insufficiency may predispose birds to the hypothyroid effects of PCBs.

Wiegand, U. W., S. Hartmann, et al. (1998). "Safety of vitamin A: recent results." Int J Vitam Nutr Res 68(6): 411-6.

A still unresolved public health concern is that excessive vitamin A intake, like vitamin A deficiency, possibly causes birth defects not only in animals but also in man. Due to the low incidence of possibly vitamin A-related malformations in man, available data cannot convincingly define the upper safe limit of periconceptional vitamin A intake. Direct human intervention studies are not feasible for ethical reasons. Therefore, a novel approach in addressing this issue was chosen by combining teratogenicity data from a validated animal model with data on systemic exposure to vitamin A and its major metabolites in female volunteers. In a study in pregnant women endogenous plasma concentrations of vitamin A metabolites during early pregnancy ranged from 0.26 to 7.72 ng/ml. Since they did not cause any foetal malformations, retinoid plasma levels in this range can be considered non-teratogenic. Results of a trial in non-pregnant women document that daily oral vitamin A supplements of 4000, 10,000 and 30,000 IU given for 3 weeks were in the range or slightly above the range of endogenous plasma levels seen in early pregnancy. Even after a 3-week treatment with 30,000 IU/day, peak plasma levels of retinoic acid and isotretinoin were within or just slightly above the range of their physiological levels. In cynomolgus monkeys (average weight: 3-4 kg), a NOAEL (no observed adverse effect level) of 7500 IU per kg body weight and a LOAEL (lowest observed adverse effect level) for developmental toxicity of 20,000 IU/kg was found. Considering these results in the cynomolgus monkey, a dose of 30,000 IU/day should also be considered as non-teratogenic in man.

Ghebremeskel, K., L. Burns, et al. (1994). "Vitamin A and related essential nutrients in cord blood: relationships with anthropometric measurements at birth." Early Hum Dev 39(3): 177-88.

Following the advice given by the Department of Health to women who are, or may become pregnant, not to eat liver and liver products because of the risk of vitamin A toxicity, the concentrations of vitamins A and E, and copper, magnesium and zinc in cord blood were investigated. The study was conducted in Hackney, an inner city area of London. Esters of vitamin A were not detected in any of the samples, indicating that there was no biochemical evidence of a risk of toxicity. Indeed, vitamin A correlated significantly with birthweight, head circumference, length, and gestation period. There was also a significant positive relationship between zinc and birthweight. In contrast, copper showed a negative correlation with birthweight and head circumference. Vitamin E and magnesium were not associated with any of the anthropometric measurements, although magnesium showed an increasing trend with birthweight. The data suggest that most of the mothers of the subjects studied may have been marginal with respect to vitamins A and E and zinc. In those with low birthweight babies. a higher intake would have improved their nutritional status and possibly the outcome of their pregnancy. For these low-income mothers, liver and liver products are the cheapest and the best source of vitamins A and E, haem iron, B vitamins and several other essential nutrients; hence the advice of the Department of Health may have been misplaced.