Abstract
The biosynthesis of retinoic acid from beta-apocarotenoic acids was examined for a beta-oxidation-like process using both rabbit liver mitochondrial fractions with various beta-apocarotenoic acids (beta-apo-14'-, beta-apo-12'-, and beta-apo-8'-carotenoic acid) and perfusion in ferret liver through the portal vein with beta-apo-8'-carotenoic acid. The in vitro incubation of beta-apo-8', beta-apo-12'-, and beta-apo-14'-carotenoic acids gave rise to shorter chain beta-apocarotenoic acids as well as retinoic acid. The rate of retinoic acid synthesis from 10 microM beta-apo-8', beta-apo-12'-, and beta-apo-14'-carotenoic acids was 11 +/- 2, 18 +/- 3, and 30 +/- 7 pmol/h/mg of protein, respectively. The stepwise oxidation of beta-apocarotenoic acid in mitochondria was dose-related to both protein concentration and substrate concentration. beta-Apocarotenoic acid oxidation was inhibited in a dose-dependent manner when it was co-incubated with oleoyl-CoA. The in vivo perfusion of ferret liver with beta-apo-8'-carotenoic acid resulted in a linear increase in the retinoic acid concentration of bile, which was completely abolished by co-perfusion of 3-mercaptopropionic acid, an inhibitor of long chain acyl-CoA dehydrogenase, and partially inhibited by 2-tetradecylglycidic acid, an inhibitor of carnitine-palmitoyl-CoA transferase I. However, the formation of retinoic acid from the beta-apocarotenoic acids was not inhibited, either in vitro or in vivo, by citral, an inhibitor of retinal oxidase. Thus, the formation of retinoic acid was not occurring by the central cleavage pathway. These data suggest that the oxidation of intermediate compounds between beta-carotene and retinoic acid may undergo a type of beta-oxidative process to form retinoic acid, which is reminiscent of mitochondrial fatty acid beta-oxidation. This pathway may play an important role in the biosynthesis of retinoic acid from beta-carotene.
Highlights
¶ To whom correspondence and reprint requests should be addressed: Gastrointestinal Nutrition Laboratory, USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St., Boston, MA 02111
We have investigated whether the mitochondrial fraction of rabbit liver could carry out the further metabolism of -apocarotenoic acids, with particular emphasis on the formation of products indicative of oxidation at the -position of each carotenoic acid, e.g. the conversion of -apo-8Ј-carotenoic acid to the 10Ј-acid, the 10Ј-acid to the 12Ј-acid, the 12Ј-acid to the 14Ј-acid, and the 14Ј-acid to 15-carotenoic acid (Fig. 1)
Since the rate of formation of each product shortened by two carbons is approximately the same when the individual -apocarotenoic acids were used as substrates, this would suggest that the methyl groups on carbons 9Ј and 13Ј do not interfere with the -oxidation-like process of -apocarotenoic acid metabolism
Summary
¶ To whom correspondence and reprint requests should be addressed: Gastrointestinal Nutrition Laboratory, USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St., Boston, MA 02111. We have shown that when purified -carotene is incubated with homogenates of small intestine and other tissues, a series of homologous carbonyl cleavage products are produced including -apo-14Ј-, -apo-12Ј-, -apo10Ј-, and -apo-8Ј-carotenal, and -apo-13-carotenone, as well as retinoic acid and retinal (-apo-15-carotenal) [16, 17] Under these experimental circumstances, the retinoic acid produced represents one-third of the total retinoids formed [2], even when citral (an inhibitor of oxidation of retinal) is added to the incubation mixture [18]. The retinoic acid produced represents one-third of the total retinoids formed [2], even when citral (an inhibitor of oxidation of retinal) is added to the incubation mixture [18] In view of these observations, we concluded that in addition to the central cleavage, an excentric cleavage mechanism is involved in the metabolism of -carotene into retinoic acid. Our results suggest that one of the mechanisms for bioconversion of -apocarotenoic acid into retinoic acid is a type of -oxidation, which is reminiscent of fatty acid -oxidation
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