Metabolism, Plasma Transport and Biliary Excretion of Radioactive Vitamin A and its Metabolites as a Function of Liver Reserves of Vitamin A in the Rat

Abstract

Groups of 7-12 weanling Sprague-Dawley male rats were fed graded daily doses of vitamin A (5-176 micrograms retinol) for 7 or 12 weeks. Final mean liver concentrations of vitamin A, which ranged from 0.4 to 331 micrograms retinol per gram, depended both on the daily dose given and on the length of the feeding period. The mean serum retinol concentration was 24 micrograms/dl at the lowest liver vitamin A concentration, approached a plateau of 40 micrograms/dl at a liver concentration of 5-10 micrograms/g, and then very slowly increased with higher levels of vitamin A in the liver. Seven days after the oral administration of a standard dose (4.6 microCi) of 11,12-[3H2]retinyl acetate, during which period rats were fed the customary vitamin A-containing diet, bile was collected via bile duct cannulae for 1-4 hours, and then the livers and serum were extracted and analyzed. The key relationships defined were: 1) that the mean ratio of specific activities of retinol in serum to that in liver was 0.65 +/- 0.05 (SEM) (range: 0.46-0.81) at daily retinol intakes of 8-176 micrograms/day, 2) that the ratio did not vary systematically with vitamin A intake or liver reserves and 3) that the mean excretion rate of vitamin A metabolites in the bile was invariant at 0.28 microgram retinol metabolites per milliliter of bile up to a liver vitamin A concentration of 32 micrograms retinol per gram, but then increased rapidly by eightfold to a maximal rate of 2.4 micrograms retinol metabolites per milliliter of bile at a liver vitamin A value of 140 micrograms retinol per gram.(ABSTRACT TRUNCATED AT 250 WORDS)

Scientific Opinion on Dietary Reference Values for vitamin A

“…To account for the fact that unlabelled retinol is continuously consumed in the diet and newly absorbed retinol contributes preferentially to the plasma pool, another factor is applied to correct for the difference in specific activity in liver compared with plasma. A value of 0.65 is usually assumed, derived from the ratio observed in rats (Hicks et al, 1984). This factor is not needed if no retinol, or as little as possible, is consumed during the equilibration period.…”

“…as free retinol and retinyl esters) as a criterion to define adequate vitamin A status, based on the following considerations: (1) no clinical signs of deficiency have been noted in individuals with this or a higher liver concentration; (2) at this concentration and above, the liver is capable of maintaining a steadystate plasma retinol concentration, as determined by the relative dose-response test in rats (Loerch et al, 1979) and humans (Amedee-Manesme et al, 1987); (3) biliary excretion of retinol increases significantly when liver stores rise significantly above this concentration in rats (Hicks et al, 1984), which is suggested to serve as a regulatory mechanism of vitamin A storage; and (4) this concentration was calculated to be sufficient to protect an adult ingesting a diet free of vitamin A from a deficiency state for approximately four months as well as to meet vitamin A needs during shorter periods of stress (e.g. infection).…”

“…A minimum acceptable liver vitamin A concentration of 20 µg/g (0.07 µmol/g) was considered. At this concentration, no clinical signs of deficiency are observed, adequate plasma retinol concentrations are maintained (Loerch et al, 1979), induced biliary excretion of vitamin A is observed (Hicks et al, 1984) and protection against vitamin A deficiency is ensured for approximately four months while consuming a vitamin A-deficient diet. The Estimated Average Requirement (EAR) was calculated by multiplying the percentage of body vitamin A stores lost per day when ingesting a vitamin A-free diet (0.5 %), the minimum acceptable liver retinol concentration (20 µg/g), the liver weight:body weight ratio (1:33), the reference weight for a specific age group and sex (61 and 76 kg for women and men, respectively), the ratio of total body:liver vitamin A stores (10:9) and the efficiency of storage of ingested vitamin A (40 %) (Olson, 1987).…”

Current Capabilities and Limitations of Stable Isotope Techniques and Applied Mathematical Equations in Determining Whole-Body Vitamin A Status

“…42 Thus, to be more broadly applicable, the correction for 12 F is a factor to express efficiency of storage (estimated to be 0. 5 49 ); S is the ratio of specific activity of retinol in plasma to specific activity of VA in liver (taken as 0.65 from a rat study 50 ); a is the fraction of absorbed tracer dose remaining in body at time t after dosing (a ¼ e Àkt , using an estimated rate of catabolism of VA for adults; k ¼ [ln 2]/140 days ¼ 0.00495 per day); H:D is the isotope ratio of nondeuterated (tracee) to deuterated (tracer) retinol in plasma; and the term ''À1'' is used to correct for the contribution of the mass of the tracer dose to the total VA stores (not needed when the tracer dose is small)…”

Evaluation of the “Olson Equation”, an Isotope Dilution Method for Estimating Vitamin A Stores

“…Furr et al included the factor S (the ratio of vitamin A specifi c activity in plasma vs. liver), estimated as 0.65, to account for the dilution of the tracer/tracee ratio as unlabeled vitamin A (tracee) enters the system from the diet, and tracer and tracee are lost by catabolism. The value for S was based on earlier studies in Olson's lab on the metabolism of vitamin A in rats as a function of liver vitamin A stores [11]. Also related to catabolism, and thus loss of tracer, the factor a was introduced as a correction.…”