Despite its potent biologic effect on human sebocytes, 13-cis retinoic acid exhibits low binding affinity for cellular retinoic acid binding proteins and nuclear retinoid receptors. Hence, 13-cis retinoic acid may represent a pro-drug possibly acting through all-trans isomerization. In this study, marked isomerization of 13-cis retinoic acid has been confirmed in cultured SZ95 sebocytes showing 2- to 15-fold higher levels of all-trans retinoic acid at 12-72 h, as measured by high performance liquid chromatography. In contrast, only low amounts of all-trans retinoic acid were converted intracellularly to its 13-cis isoform. 9-cis retinoic acid was not detected after either 13-cis retinoic acid or all-trans retinoic acid treatment. The rapid isomerization of 13-cis retinoic acid to high levels of all-trans retinoic acid was a sebocyte-specific event, as no significant isomerization of 13-cis retinoic acid to all-trans retinoic acid occurred in HaCaT keratinocytes. De novo mRNA expression of cytochrome P450 1A1, a major xenobiotic metabolizing enzyme, in SZ95 sebocytes was induced by all-trans retinoic acid, but not by 13-cis retinoic acid. In addition, mRNA levels of cellular retinoic acid-binding protein II, which is supposed to regulate the concentration of intracellular all-trans retinoic acid, rapidly increased under all-trans retinoic acid treatment (30 min-6 h), whereas the 13-cis retinoic acid effect was markedly weaker and delayed. Both 13-cis retinoic acid and all-trans retinoic acid suppressed mRNA expression of cytochrome P450 1A2. In parallel experiments, 13-cis retinoic acid significantly reduced SZ95 sebocyte proliferation at 10-7 M, show- ing 30-40% inhibition after 9 d. All-trans retinoic acid and 9-cis retinoic acid exhibited similar anti-proliferative effects. AGN 193109, a pan-antagonist of the retinoic acid receptors, antagonized the anti-proliferative activity of all retinoic acid isomers tested in a concentration-dependent manner with complete abolishment at ratios of 1:10 13-cis retinoic acid and 1:1 all-trans retinoic acid. Coincubation of SZ95 sebocytes with 13-cis retinoic acid and AGN 193109 did not alter the intracellular concentration of 13-cis retinoic acid and its isomerization profile. In contrast, the retinoid X receptor antagonist CD 3507 did not affect the inhibition of SZ95 sebocyte proliferation induced by retinoic acids. Our findings indicate: (i) a selective 13-cis retinoic acid isomerization to all-trans retinoic acid in the intracellular compartment of SZ95 sebocytes; (ii) a reduced all-trans retinoic acid inactivation process after 13-cis retinoic acid treatment as compared with treatment with all-trans retinoic acid; and (iii) a retinoic acid receptor-mediated inhibition of SZ95 sebocyte proliferation. These data explain the sebocyte-specific activity of 13-cis retinoic acid and support a pro-drug/drug relation between 13-cis retinoic acid and all-trans retinoic acid.