The biosynthesis of D-ring fatty acid esters of estriol

Biological esterification with fatty acids is a feature that is now known to be common to most steroids. The esterification of estradiol in the D-ring at the 17 beta-hydroxyl leads to a family of extremely active estrogens. Similarly, esterification of the weaker estrogen, estriol (E3), has an even greater impact on its hormonal potency. We have recently shown that synthetic long chain esters of E3 at either 16 alpha- or 17 beta- are highly potent estrogens. The estrogenic activity of the synthetic E3 esters led us to determine whether E3 is biologically esterified, and if so, to characterize the resulting esters. Incubation of E3 with rat lung, a tissue which is highly active in esterifying estradiol, produces a nonpolar metabolite which upon saponification is converted back into E3. There was no evidence for the formation of a diester. Purification by high performance liquid chromatography separates the non-polar metabolite into two peaks, one the C-16 alpha- (approximately 60%) and the other the C-17 beta-ester (approximately 40%). The two fractions were further purified and characterized; each is a mixture of fatty acid esters of E3. The composition of the C-16 alpha- and the C-17 beta-fatty acid esters of E3 is identical. The predominant fatty acids are arachidonate, 34%, palmitate, 26%, followed by oleate 14%, linoleate 13%, stearate 8%, and palmitoleate 5%. The similarity of the esters at C-16 and C-17 may indicate that the fatty acid precursor for the acyltransferase is the same for both hydroxyl groups. It may also suggest that the same enzyme esterifies both positions in the D-ring. Since synthetic estriol fatty acid esters are extremely potent and long-lived estrogens, the enzymatic esterification of estriol produces powerful estrogens with considerable physiological potential.