The synthesis, biological activity and metabolism of 15-[6,7-14C2]- and 15-[21-3H]methyl retinone, 15-methyl retinol and 15-dimethyl retinol in rats.
15-Methyl retinone, 15-methyl retinol and 15-dimethyl retinol were synthesized from all-trans retinoic acid. The absorption maxima and molar absorption coefficients (epsilon) in ethanol are: 15-methyl retinone (372 nm, 47 400), 15-methyl retinol (325 nm, 72 000) and 15-dimethyl retinol (325 nm, 72 200). The latter two compounds show fluorescence at 470 nm when excited around 320 nm, but with intensities 40 and 70%, respectively, that of retinol. All react with trifluoroacetic acid in chloroform, and the alcohols are dehydrated in ethanolic HCl. Relative to all-trans retinyl acetate, the biological activities in rat growth assay (+/-S.E.) are: 15-methyl retinone (4.7 +/- 1.5%), 15-methyl retinol (16.2 +/- 2.3%) and 15-dimethyl retinol (0.34 +/- 0.07%). The monomethyl derivatives actively support testicular development and spermatogenesis, but none of the three analogues prevents degeneration of the retina in retinoate-treated vitamin A-deficient rats. By using [6,7-14C2]-, [11,12-3H2]- and [21-3H]-labeled analogues, the 15-methyl derivatives were shown to be well absorbed in the gut but poorly stored (1-3% of the dose) in the liver. Metabolites are excreted extensively (25-65%) in the bile, however, largely as glucuronides, and to some extent (15%) in the urine. 15-Methyl retinone is reduced to 15-methyl retinol in the intestinal mucosa but not in the liver, and fatty acyl esters of the alcohols are present in liver. Insofar as we could judge, none of these 15-methyl analogues is converted into retinol. Both monomethyl and dimethyl retinols are transported in plasma in vivo in the retinol-binding protein fraction. Interestingly, the dosages required for half saturation and saturation of the plasma transport system are inversely related, in a rough way, to the biological activities in growth.
D000818:Animals; D001646:Bile / Q000378:metabolism; D004224:Diterpenes; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D012160:Retina / Q000378:metabolism; D013737:Testis / Q000378:metabolism; D014018:Tissue Distribution; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000378:metabolism; D014802:Vitamin A Deficiency / Q000378:metabolism
D004224:Diterpenes; D014801:Vitamin A; C017520:15-methyl retinone; C017519:15-methyl retinol