Constant variation in structure and function of geometrical isomers of acitretin under natural light

Abstract

Acitretin, a beneficial retinoid, was shown to undergo constant structural interconversions among its geometrical isomers (all-<i>trans</i>-acitretin, 9-<i>cis</i>-acitretin, 13-<i>cis</i>-acitretin, 9, 13-di-<i>cis</i>-acitretin, etc.) by photoisomerization under natural light. The photoisomerization was zero order reaction with an apparent velocity of 4×10^-7 <i>M/</i>min<i> </i>under illumination by

white fluorescent lamps (1, 200 1x). An equilibrium mixture of the geometrical isomers (all<i>-trans-</i>acitretin<i> </i>20%, 9<i>-cis-</i>acitretin 15%, 13-<i>cis</i>-acitretin 30%, 9, 13-di-<i>cis</i>-acitretin 15%, and unidentified compounds 20%) was formed at around 30 min. Equilibrium mixtures with similar composition were obtained by photoisomerization reactions starting from other

geometrical isomers. Geometrical isomers of acitretin thus formed, showed different effects to induce differentiation of human acute promyelocytic leukemia cells (HL-60 cells): activity of all-<i>trans</i>-acitretin (ED₅₀, 3.2×10^-6<i>M</i>), 9-<i>cis</i>-acitretin (ED₅₀, 2.3×10^-5<i>M</i>), 13-<i>cis</i>-acitretin (ED₅₀, 1.1×10^-5<i>M</i>),<i> </i>9, 13-di-<i>cis</i>-acitretin (ED₅₀, 2.6×10^-6<i>M</i>) 9-<i>cis</i>-Acitretin acted synergistically with all-<i>trans</i>-acitretin, 13-<i>cis</i>-acitretin and 9, 13-di-<i>cis</i>-acitretin on HL-60 cells. On the other side, all<i>-trans-</i>acitretin, 13-<i>cis</i>-acitretin and 9, 13-di-<i>cis</i>-acitretin acted additively. Geometrical isomers of acitretin showed different effects on differentiation of human epidermal keratinocytes; expression of keratinocyte differentiation markers, keratin 1 and kerati 10, were suppressed more strongly by 9-<i>cis</i>-acitretin and 13-<i>cis</i>-acitretin as compared to all-<i>trans</i>-acitretin or 9, 13-di-<i>cis</i>-acitretin.