102 Biochimica et Biophysica Acta, 1055 (1990) 102-106 Elsevier BBAMCR 12800 Uptake of the aromatic retinoids Ro 10-9359 (etretinate) and Ro 10-1670 (acitretin), its main metabolite, delivered to cultured human fibroblasts by serum proteins. Lack of evidence for perturbation of LDL catabolism Vrronique Carillet 1, Patrice Morli~re 1, Jean-Claude Mazi~re 2,3, Gabriele Hiippe 1, Ren6 Santus 3 and Louis Dubertret 1 J Laboratoire de Dermatologie, I N S E R M U. 312, HOpital Henri Mondor, Cr&eil, 2 Laboratoire de Biochimie, FacultO de M~decine Saint Antoine, Paris and 3 Laboratoire de Physico-Chimie de l'Adaptation Biologique, I N S E R M U. 312, Museum National d'Histoire Naturelle, Paris (France) (Received 29 January 1990) Key words: Retinoid; Serum protein; Cellular uptake; LDL catabolism Etretinate or acitretin are efficiently delivered to cultured human fibroblasts in the presence of low density lipoproteins, high density lipoproteins or human serum albumin. In contrast to acitretin, delivery of etretinate to fibrobasts is more efficiently achieved with human serum albumin than with lipoproteins. The uptake of etretinate and acitretin via low density lipoproteins delivery, does not take place via the low density lipoprotein-receptor endocytotic pathway but mostly through a passive exchange with the plasma membrane. However, in contrast to acitretin, the exchange of etretinate seems to occur alter binding of etretinate-loaded low density lipoproteins to the apolipoprotein B receptors. No differences are observed in binding, internalization and degradation of native, etretinate-loaded low density lipoproteins and acitretin-loaded low density lipoproteins, suggesting that the presence of these retinoids in low density lipoproteins does not alter their processing by the cells. Furthermore, the presence of these retinoids in the cells does not notably affect, under our experimental conditions, the catabolism of native low density lipoproteins. Introduction Etretinate (Ro 10-9359; Tegison in U.S.A., Tigason in Europe) is an aromatic synthetic retinoid (see molec- ular structure in the companion paper [1]) prescribed in treatment of all forms of dermatosis which are charac- terized by disorders of keratinization [2]. Due to its high Abbreviations: DMEM, Dulbecco's modified minimum essential medium; EMEM, Earle's modified minimum essential medium; LDL, low density lipoprotein; HDL, high density lipoprotein; HSA, human serum albumin; Tris, Tris-buffered saline; LDL/E, low density lipo- protein loaded with etretinate; LDL/E*, low density lipoprotein loaded with [14C]etretinate; HDL/E*, high density lipoprotein loaded with [14C]etretinate, HSA/E*, human serum albumin loaded with [14C]etretinate; LDL/A, low density lipoprotein loaded with acitre- tin; LDL/A*, low density lipoprotein loaded with [14C]acitretin; HDL/A*, high density lipoprotein loaded with [14C]acitretin; HSA/A*, human serum albumin loaded with [14C]acitretin; 125I-LDL, 125I-labelled low density lipoprotein. Correspondence: P. Morli~re, Laboratoire de Dermatologie, INSERM U.312, Hrpital Henri Mondor, 94010 Cr&eil, France. hydrophobicity, etretinate is extremely slowly eliminated after storage in adipose tissue [3]. In humans, natural and therapeutically administered retinoids are found in the skin and are distributed between epidermis, dermis and subcutis [4]. Studies of the etretinate fate in cul- tured human epidermal cells show that both keratino- cytes and fibroblasts can metabolize etretinate leading to acitretin (Ro 10-1670) [3,5] (see molecular structure in the companion paper [1]). Acitretin is as effective as etretinate in psoriasis [6] and is eliminated faster than the ester parent compound [7]. Both retinoids have a large plasma protein-binding capacity. Lipoproteins and albumin are potential serum carriers of retinoids [1,8] and previous reports mentioned that retinoids are not transported by the retinol-binding protein [7,9]. Among side effects of retinoid treatment [10,11] elevation of blood triacylglycerol, total cholesterol and low density lipoprotein cholesterol levels, as well as significant de- creases of high density lipoprotein cholesterol have been reported [12-15]. Thus, we studied using low density lipoproteins (LDL), high density lipoproteins (HDL) or human 0167-4889/90/$03.50 © 1990 Elsevier Science Pubfishers B.V. (Biomedical Division)