4- Hydroxyretinoic acid

The conventional numbering of carbon atoms in the retinoid molecule is shown in the structure of retinol (I). On the basis of this numbering scheme, geometric isomers and substituted compounds can be named unambiguously, e.g., 13-cis retinoic acid (IV), 3-hydroxyretinoic acid (V), and 9-cis retinoic acid (VI). 

X-Ray Crystallography. The X-ray crystal structure of the hydroxyretinoic acid y-lactone (230) has been determined.91 A near s-cis arrangement is reported for the C-6—C-7 bond. The polyene chain is virtually planar but buckled near the centre, the cyclohexene ring is twisted 46.3° out of the plane of the chain, and the planar butenolide ring makes an angle of 11.3° with the plane of the chain. 

Figure 2.1. Major physiologically active retinoids. Relative molecular masses (Mr) retinol, 286.5 retinaldehyde, 284.4 retinoic acid, 300.4 13,14-dihydroxy-retinol, 318.5 4-oxoretinol, 301.5 retroretinol, 286.5 14-hydroxy-retroretinol, 302.5 anhydroretinol, 269.6 4-oxo-retinoic acid, 315.4 4-hydroxyretinoic acid, 316.4 dehydroretinol, 284.4 retinyl acetate, 328.5 and retinyl palmitate, 524.9. 

Metabolism. A survey of the metabolic transformation of carotenoids by animals is included in the review by Fox. 4-Hydroxyretinoic acid (187) and 4-oxoretinoic acid (188) have been identified as metabolites of retinoic acid a l-trans and 3-cis) by hamsters, and hamster liver microsomes. ... 

The mixture of isomeric ethyl esters formed in the Wittig reaction was subjected to alkaline hydrolysis and isomerization to give pure 4-oxoretinoic acid (188), which was reduced with sodium borohydride to give 4-hydroxyretinoic acid (187) (Hanni and Ryser, 1979). 

Further treatment with phosphorus trichloride, and subsequent treatment in an aqueous medium, gave an equilibrium mixture of a-hydroxyretinoic acid (511) and a-ketoretinoic acid (512). 

Fig. 3. Chromatogram of the methyl esters of three polar metabolites of all-tra/i5-retinoic acid Column, Partisil PXS (5 p-m) mobile phase, hexane 2-propanol (99.5 0.5), flow rate, l.l ml/min peak (1) l3-c -4-oxoretinoic acid methyl ester peak (2) all-/ra/t 4-oxoretinoic acid methyl ester peak (3) all-rranj-4-hydroxyretinoic acid methyl ester. (C. A. Frolik, unpublished results.)...

Chromanetics ODS (5 p-m) mobile phase, acetonitrile acetic acid (0.1%) (42 58) flow rate, 1.2 ml/min peak (5A) all-fr 5-4-hydroxyretinoic acid (D3) peak (5B) unidentified peak (5C) 13-m-4-oxoretinoic acid peak (5D) all-/raws-4-oxoretinoic acid (D4). (Reprinted with permission from Froliketfl/., 1980.)... 

Two common metabolites of retinoic acid are 4-hydroxyretinoic acid and 4-oxoretinoic acid. In addition, 5,6-monoepoxyretinoic acid is formed as a side product in the chemical synthesis described below. 

Fig 7. Absorption spectra of a -trans 4-oxoretinoic acid (-4-hydroxyretinoic acid ( ) in methanol... 

Saponification of Methyi Esters to 4-Oxoretinoic Acid, 4-Hydroxyretinoic Acid, and 5,6-Epoxyretinoic Acid... 

The further metabolism of 13-cw-retinoic acid has been investigated in the hamster, the rat, and the human. In the normal hamster, 13-cis-4-oxoretinoic acid has been detected in the plasma 2 h after an intravenous 5.3-p.g dose of labeled 13-cts-retinoic acid (Frolik et al., 1980). As mentioned earlier, when 5.1 tg of all-rra/ -retinoic acid was injected into hamsters, the 13-cu-4-oxo metabolite and not the corresponding all-trans analog was detected. It has therefore been concluded that this metabolite is common to both isomers of retinoic acid. A basic difference, however, is that 13-ci.r-4-oxoretinoic acid is a major metabolite in the 13-cu-retinoic acid-dosed hamster, representing 21% of the radioactive metabolites in the plasma compared to 2.2% in the all-trun -retinoic acid-dosed animals (Frolik et al., 1980). In the same study, l3-cis-4-hydroxyretinoic acid was also tentatively identified. 

---