ISOMERIZATION OF ALL-TRANS-RETINOIC ACID TO 9-CIS-RETINOIC ACID

The discovery of the biological activity of 9-cis-retinoic acid raises questions as to its mode of biosynthesis. A simple mechanism involves the direct isomerization of all-trans-retinoic acid to 9-cis-retinoic acid. It is shown here that bovine liver membranes, but not supernata nt fractions, can isomerize all-trans-retinoic acid into 9-cis-retinoi c acid and 13-cis-retinoic acid. The concentration of 9-cis-retinoic a cid generated approaches its equilibrium concentration, which is deter mined here to be approximately 15%. However, the isomerization process could not be shown to be saturable, and is first-order in all-trans-r etinoic acid in the concentration range measured (8.3 nM to 3 mu M). I somerization reactions measured using bovine liver microsomes appear t o be mediated by thiol groups, as they can be blocked by group-specifi c thiol-blocking reagents such as N-ethylmaleimide. It is interesting to note that the non-stereospecific behaviour observed here mimics wha t is observed when all-trans-retinoic acid is applied to cells. Finall y, significant formation of 9-cis-retinoids was not found when the rea ction was carried out with liver microsomes and either all-trans-retin ol or all-trans-retinal.