Studies on the in vivo metabolism of retinoic acid in the rat

Abstract

A time study of the metabolism of 6,7‐14C‐retinoic acid after intraperitoneal injection of physiological levels (17 μg, 0.39 μc) into vitamin A deficient rats, which had been repleted with retinoic acid for two weeks up to two days before injection, resulted in a rapid metabolism to more polar compounds in the small intestine and its contents and a slower metabolism to primarily different materials in the liver and kidney. The major route of metabolism resulted in the urinary excretion of 60% of the injected dose in 24 to 27 hr. Urinary metabolites of 15‐14C‐retinoic acid were eluted from silicic acid at a similar concentration of solvents as the ring labeled metabolites although only 32% of the injected dose was recovered in 24 hr. Compounds chromatographically similar to the urinary metabolites were observed at various times in the liver, kidney and small intestine plus contents in addition to retinoic acid and other metabolites. The relative amounts of the metabolites in the different tissues studied varied as a function of the tissue and the time of analysis after injection. Most of the radioactivity from all tissues was extractable into methanol. A liver subcellular distribution of the radioactivity derived from the intraperitoneal injection of 650 μg of 6,7‐14C‐retinoic acid (25.9 μc) after 3 hr indicated a minimal level of association of radioactivity (150–250 dpm/mg protein) with all fractions and a greater association of radioactivity with the lysosomal‐microsomal fraction (300–350 dpm/mg protein) and the 60–100% ammonium sulfate precipitable (750–800 dpm/mg protein) and 100% ammonium sulfate soluble fractions (422 dpm/mg protein) of the soluble supernatant.

Identification of 5,8-oxyretinoic acid isolated from small intestine of vitamin A-deficient rats dosed with retinoic acid.

“…The major component, peak 811 (11.6 ,ug), was chromatographed on a microparticulate silica gel column (0.4 X 50 cm) that was developed with 0.1% formic acid in 7% tetrahydrofuran/hexane. Recovered peak 8ii (9 Mug) was methylated with diazomethane and rechromatographed on the microparticulate silica gel column with 2.5% tetrahydrofuran/hexane to yield 7 ,g of methyl 8II. 81I and the corresponding methyl 8Ii were homogeneous in the last two high-pressure liquid chromatography systems, as demonstrated by ultraviolet absorbance (313 nm) and radioactivity.…”

“…In the article "Large T1 oligonucleotides of Mo (6) because retinoic acid is not stored but is rapidly metabolized (7)(8)(9). Several biologically active metabolites of retinoic acid have been reported (10,11), but only 13-cis-retinoic acid (12) has been isolated in pure form and identified.…”

“…Ito and coworkers (15) described several retinoic acid metabolites more polar than the parent compound. The three major metabolites were designated as peaks 8,9, and 10. Peak 8 was found in liver, kidney, blood, skin, and intestine, whereas peaks 9 and 10 were found only in intestine.…”

Metabolism of 5,6-epoxyretinoic acid in vivo: isolation of a major intestinal metabolite

“…It is also more active than retinol in directing differentiation in vitro, by at least an order of magnitude (Sporn et al, 1976;Strickland & Mahdavi, 1978), but unlike retinol, it does not support vision or mammalian reproduction (Dowling & Wald, 1960;De Luca, 1978;Goodman, 1980). Retinoic acid undergoes rapid metabolism in vivo (Fidge et al, 1968;Geison & Johnson, 1970) to several more polar metabolites but not in kidney of vitamin A deficient rats. Its concentration was greatly diminished in liver and small intestinal mucosa, and it was not observed in kidney of vitamin A deficient rats dosed orally with retinoic acid for several days before administration of 5,6-epo~y[~H]retinoic acid.…”

The plasma transport and metabolism of retinoic acid in the rat

“…Very little information is available on the metabolic history ofretinoic acid. Orally administered retinoic acid is mainly adsorbed by the portal route (Fidge et al, 1968) and then rapidly metabolized, largely to more-polar compounds excreted in the urine (Geison & Johnson, 1970) and the bile (Zachman et al, 1966;Fidge et al, 1968). The major metabolite in rat bile has been identified as retinoyl fl-glucuronide (Dunagin et al, 1965).…”