PT  - JOURNAL ARTICLE
AU  - Tadao Maeda
AU  - Lindsay Perusek
AU  - Jaume Amengual
AU  - Darwin Babino
AU  - Krzysztof Palczewski
AU  - Johannes von Lintig
TI  - Dietary 9-cis-β,β-carotene Fails to Rescue Vision in Mouse Models of Leber Congenital Amaurosis
AID  - 10.1124/mol.111.074732
DP  - 2011 Jan 01
TA  - Molecular Pharmacology
PG  - mol.111.074732
4099  - http://molpharm.aspetjournals.org/content/early/2011/08/23/mol.111.074732.short
4100  - http://molpharm.aspetjournals.org/content/early/2011/08/23/mol.111.074732.full
AB  - Synthetic 9-cis-stereoisomers of vitamin A (all-trans-retinol) are especially promising agents for the fight against blinding diseases. Several studies suggest that 9-cis-β,β-carotene (9-cis-BC), a natural and abundant BC isomer in the diet, could be precursor of 9-cis-retinoids and thus could have therapeutic applications. Here we showed that 9-cis-BC is metabolized both in vitro and in vivo by two types of mouse carotenoid oxygenases, β,β-carotene monooxygenase 1 (BCMO1) and β,β-carotene dioxygenase 2 (BCDO2). In the symmetric oxidative cleavage reaction at C15,C15’ position by BCMO1, part of the 9-cis-double bond was isomerized to the all-trans-stereoisomer, yielding all-trans-retinal and 9-cis-retinal in a molar ratio of 3 to 1. The asymmetric cleaving enzyme BCDO2 preferentially removed the 9-cis-ring site at the C9,C10 double bond from this substrate providing an all-trans--β-10'-apocarotenal product that can be further metabolized to all-trans-retinal by BCMO1. Studies in knockout mouse models confirmed that each carotenoid oxygenase can metabolize 9-cis-BC. Accordingly, treatment of mouse models of Leber congenital amaurosis (LCA) with 9-cis-BC and 9-cis-retinyl-acetate (9-cis-R-Ac), a well-established 9-cis-retinal precursor, showed that the cis-carotenoid was far less effective than the cis-retinoid in rescuing vision. Thus our in vitro and in vivo studies revealed that 9-cis-BC is not a major source for mouse 9-cis-retinoid production but is mainly converted to all-trans-retinoids to support canonical vitamin A action.