The long-term goal of the research is to determine the effects of carotenoids on vitamin A homeostasis. Vitamin A nutriture is inversely related to the incidence of tumors induced in experimental animals, but chronic dosing with higher levels of vitamin A produces toxicity. Beta-carotene is a non-toxic source of vitamin A and may have anti-tumor activity in its own right. This application addresses the hypothesis that dietary beta- carotene provides higher concentrations of naturally-occurring retinoids in tissues than does preformed vitamin A. The phenomenon is possible because the first retinoid product of beta- carotene metabolism is retinal. Retinal is converted reversibly into retinol and irreversibly into retinoic acid. The rate-limiting step of retinoic acid synthesis is dehydrogenation of retinol; the subsequent conversion of retinal into retinoic acid is faster and more extensive. Thus two mechanisms, independent of the well- studied liver model of vitamin A homeostasis, are available for beta-carotene to affect tissue retinoids. Production in situ by extra-hepatic tissues of retinol from beta-carotene would circumvent the physiologically-controlled delivery of retinol. Production of retinoic acid from beta-carotene in the intestine, and in extra-intestinal tissues, would by-pass the rate-limiting step in retinoic acid sythesis. Retinoic acid will be a focus of this work because it is more potent generally than retinol in stimulating the differentiation of basal and tumorigenic cells into non-tumorigenic and specialized phenotypes.
The Specific Aims are: 1) determine the effects of dietary beta- carotene on the concentrations of retinoic acid, retinol and retinyl esters in the serum and tissues of rats fed beta-carotene as their sole source of vitamin A and as a supplement to vitamin A: 2) determine the conditions of retinoic acid synthesis from beta-carotene by intestine, the relative quantities of retinoic acid and retinol produced, and the fate of the retinoic acid; 3) identify tissues that convert beta-carotene into retinoids and determine whether dietary beta-carotene affects the rate of conversion. Assays specific for individual retinoids, based on high- performance liquid chromatography and gas-chromatography/mass spectrometry, will be used to quantify retinoids.
| Napoli, J L (1993) Retinoic acid synthesis from beta-carotene in vitro. Methods Enzymol 214:193-202 |
| Napoli, J L (1990) Quantification and characteristics of retinoid synthesis from retinol and beta-carotene in tissue fractions and established cell lines. Methods Enzymol 189:470-82 |
| Posch, K C; Enright, W J; Napoli, J L (1989) Retinoic acid synthesis by cytosol from the alcohol dehydrogenase negative deermouse. Arch Biochem Biophys 274:171-8 |
| Napoli, J L; Race, K R (1988) Biogenesis of retinoic acid from beta-carotene. Differences between the metabolism of beta-carotene and retinal. J Biol Chem 263:17372-7 |
