Effect of retinoic acid and apo-RBP on serum retinol concentration in acute renal failure.

We recently demonstrated a rapid up-regulation of serum retinol-retinol binding protein-transthyretin concentration in rats with short-term acute renal failure. We examine the effect of retinoic acid and apo-retinol binding protein (apo-RBP) on the up-regulation of serum retinol in renal failure. Injection of retinoic acid (10 micrograms) into rats with acute renal failure or sham-operated rats increased circulatory retinoic acid concentration 29-fold within 2 h but did not influence serum retinol concentration in either group. Injection of a large dose of retinoic acid (100 micrograms) decreased serum retinol concentration in rats with acute renal failure (19%) and sham-operated rats (29%). These results suggest that changes in serum retinoic acid concentration within the near-physiological range have no effect on regulation of hepatic retinol release. Injection of a large dose of retinoic acid may depress serum retinol indirectly via a retinol sparing effect in target tissues. In rats with renal failure the serum retinol concentration, elevated 44-52% above that of sham-operated controls, was also increased to 70-164% above controls by the injection of 52-63 micrograms of apo-RBP. This suggests that circulatory apo-RBP can up-regulate serum retinol. Circulatory apo-RBP may be a positive physiological feedback signal from peripheral tissues for hepatic release of retinol.

Effect of dietary retinoic acid on circulatory vitamin A homeostasis in polybrominated biphenyl-treated rats.

Retinoic acid (RA) supplementation is known to lower the amount of retinol in circulation. In contrast, the feeding of polyhalogenated aromatic hydrocarbons results in an elevated level of circulatory retinol. We investigated the effect of short-term dietary exposure to RA on the amount of serum retinol in female Sprague-Dawley rats fed either a basal diet (control rats) or the basal diet containing 100 mg of polybrominated biphenyls (PBBs)/kg diet (PBB-treated rats). After feeding of the above diets for 137 d, RA (12 mg/kg diet) was included in both the control and PBB-containing diets. The rats were fed the RA-containing diet for 3 d and then killed (d 140). Blood samples were obtained before and after RA treatment. Chronic PBB treatment of rats resulted in lower hepatic vitamin A and higher kidney vitamin A than in control rats. Serum retinol concentration was significantly higher in rats treated with PBB for 137 d than in controls; the subsequent treatment with RA lowered serum retinol to a level that was not different from that of control rats treated with RA. Our observations agree with earlier findings that 1) PBB treatment alters vitamin A homeostasis, and 2) dietary RA lowers the amount of circulatory retinol. An important new observation is that serum retinol homeostasis in PBB-treated rats appears to be regulated by a mechanism similar to that of normal rats. Polyhalogenated aromatic hydrocarbons may thus be useful tools to study the control mechanisms of vitamin A homeostasis.

Effect of moderate vitamin A supplementation and lack of dietary vitamin A on the development of mammary tumors in female rats treated with low carcinogenic dose levels of 7,12-dimethylbenz(a)anthracene.

We examined the effect of moderately increased and of marginal continued dietary supplementation of vitamin A (retinyl acetate) and the effect of lack of dietary vitamin A on the initiation and promotion stages of mammary tumorigenesis in female Sprague-Dawley rats treated with a single low (0.5 mg/100 g body weight) or very low (0.1 mg/100 g body weight) dose of i.v.-administered 7,12-dimethylbenz(a)anthracene. The number of mammary tumors was significantly (P less than 0.05) reduced if prior to and during initiation with 7,12-dimethylbenz(a)anthracene the rats were fed a moderately increased (30 micrograms/day) or marginal (3 micrograms/day) amount of vitamin A, compared to rats fed an adequate (10 micrograms/day) amount of vitamin A. The number of mammary tumors was also significantly (P less than 0.05) reduced when a moderately increased or marginal amount of vitamin A was provided during the tumor promotion phase. In addition, the number of mammary tumors was significantly (P less than 0.05) reduced by the lack of dietary vitamin A during both the initiation and promotion stages of this tumorigenic process, when compared to vitamin A adequate, ad libitum-fed rats, but not when compared to vitamin A adequate, food-restricted controls. The reduction in numbers of mammary tumors observed in these studies was reflected primarily in significant (P less than 0.05) decreases in mammary fibroadenomas; the number of mammary carcinomas was often reduced, but due to a low frequency of the carcinomatous lesions, this reduction did not reach the 5% level of statistical probability. Plasma and liver vitamin A levels were determined during both the initiation and promotion stages. As the dietary supplementation of vitamin A increased from 0 to 30 micrograms/day, there was an increase in mean liver and plasma vitamin A levels. No consistent correlation between plasma and liver vitamin A levels and the occurrence of mammary tumors was observed, except with the moderately increased (30 micrograms/day) intake of vitamin A, that resulted in a small, but statistically significant (P less than 0.05) increase of serum retinol at initiation; this may account for the observed reduction in mammary tumors. These results provide evidence that moderate alterations in vitamin A consumption can modulate low-dose chemically induced mammary gland tumorigenesis. Most importantly, suppression of mammary gland tumorigenesis can be achieved by moderately increased, frequent, and regular consumption of vitamin A; prolonged consumption of vitamin A-deficient diets or diets marginal in vitamin A does not enhance the risk of mammary tumor development.