isotretinoin and 4-(2-(5-6-7-8-tetrahydro-5-5-8-8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic-acid

Hypertriglyceridemia is a metabolic complication of retinoid therapy. In this study, we analyzed whether retinoids increase the expression of apo C-III, an antagonist of plasma triglyceride catabolism. In men, isotretinoin treatment (80 mg/d; 5 d) resulted in elevated plasma apo C-III, but not apo E concentrations. In human hepatoma HepG2 cells, retinoids increased apo C-III mRNA and protein production. Transient transfection experiments indicated that retinoids increase apo C-III expression at the transcriptional level. This increased apo C-III transcription is mediated by the retinoid X receptor (RXR), since LG1069 (4-[1-(5,6,7,8-tetrahydro-3,5,5,8, 8-pentamethyl-2-naphtalenyl)ethenyl]benzoic acid), a RXR-specific agonist, but not TTNPB ((E)- 4-[2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphtalenyl)propenyl]benzoic acid), a retinoic acid receptor (RAR)-specific agonist, induced apo C-III mRNA in HepG2 cells and primary human hepatocytes. Mutagenesis experiments localized the retinoid responsiveness to a cis-element consisting of two imperfect AGGTCA sequences spaced by one oligonucleotide (DR-1), within the previously identified C3P footprint site. Cotransfection assays showed that RXR, but not RAR, activates apo C-III transcription through this element either as a homo- or as a heterodimer with the peroxisome proliferator-activated receptor. Thus, apo C-III is a target gene for retinoids acting via RXR. Increased apo C-III expression may contribute to the hypertriglyceridemia and atherogenic lipoprotein profile observed after retinoid therapy.

Topics: Adult; Apolipoprotein C-III; Apolipoproteins C; Benzoates; Bexarotene; Carcinoma, Hepatocellular; Cells, Cultured; Dimerization; Double-Blind Method; Gene Expression Regulation; HeLa Cells; Humans; Hypertriglyceridemia; Isotretinoin; Liver; Liver Neoplasms; Male; Mutagenesis, Site-Directed; Promoter Regions, Genetic; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Regulatory Sequences, Nucleic Acid; Retinoid X Receptors; Retinoids; Tetrahydronaphthalenes; Transcription Factors; Transcription, Genetic; Transfection; Tumor Cells, Cultured

A panel of retinoid compounds (tretinoin, isotretinoin, acitretin, and RO13-1470) were tested for inhibitory activity against Kaposi's sarcoma cell (KSC) cultures in vitro. Tretinoin was found to be the most effective retinoid tested, inhibiting the growth of KSC in vitro while having no effect on the expression of interleukin-6 and basic fibroblast growth factor, two important cytokines involved in KSC growth. Tretinoin also did not appear to downregulate the expression of receptors for these two cytokines. At low concentrations (10(-9) M), acitretin and tretinoin selectively inhibited growth of early passage KSC. At higher concentrations (10(-6)-10(-5) M), retinoid treatment induced a pattern of DNA degradation and morphological changes in KSC characteristic of apoptosis (programmed cell death). The inhibitory activity of tretinoin on KSC growth was decreased if human serum (but not fetal calf serum) was present in the growth medium, and partially restored by removal of serum lipids. These data suggest that retinoids possess potential as therapeutic agents in Kaposi's sarcoma.

Topics: Acitretin; Benzoates; Cell Division; Fibroblast Growth Factor 2; Humans; Interleukin-6; Isotretinoin; Male; Receptors, Fibroblast Growth Factor; Receptors, Interleukin; Receptors, Interleukin-6; Retinoids; RNA, Messenger; Sarcoma, Kaposi; Tretinoin; Tumor Cells, Cultured

Isotretinoin differs from acitretin and Ro137410 by its striking sebostatic effect in acne after oral, but not topical, administration. The reason for this is not yet understood. Previous studies indicate that cellular retinoic acid binding protein (CRABP) might be implicated in the action of synthetic retinoids. We, therefore, compared the three retinoids for their ability to increase epidermal CRABP levels after systemic and topical treatment. Oral treatment with acitretin and Ro137410 led to a striking increase of epidermal CRABP (from 2.6 +/- 0.9 to 16.2 +/- 2.9, P less than 0.004 and from 2.5 +/- 1.2 to 21.5 +/- 3.4 pmol/mg protein, P less than 0.004, respectively), while isotretinoin failed to induce a comparable rise (3.2 +/- 1.6 before and 3.7 +/- 0.7 pmol/mg protein after treatment), although it displayed in all patients a striking sebostatic effect. After topical application, the increase of CRABP was comparable for all three compounds. The interaction of isotretinoin with the epidermis seems to be different from other synthetic retinoids only after systemic treatment, a finding that parallels clinical observations.

Topics: Acitretin; Acne Vulgaris; Administration, Oral; Administration, Topical; Adolescent; Adult; Aged; Benzoates; Carrier Proteins; Female; Humans; Isotretinoin; Male; Middle Aged; Receptors, Retinoic Acid; Retinoids; Skin; Time Factors; Tretinoin