We showed previously that retinoids stimulate apolipoprotein A-I (apoA- I) synthesis in cultured cynomolgus hepatocytes only after a 24-h lag phase. Here we report on the biochemical background of the slow response, the requirement for high retinoic acid concentrations, and the involvement of different retinoid receptors. The time course of the effect of 10 uM all- trans retinoic acid (at-PA) on apoA-I mRNA levels and protein secretion were comparable, i.e., minor increases were observed after a 24-h incubation and mRNA levels were increased 2.2- and 3.5-fold after 48 h and 72 h, respectively. In contrast, apoA-I gene transcription was already increased (2.6-fold) after a 4-h incubation with 10 uM at-RA. At-RA disappeared rapidly from the cultures: after 2 h of incubation 40% of the added amount was left and after 24 h only 2%. RARbeta mRNA and gene expression were increased after incubation with 10 nm at-RA, whereas RARer and RXRalpha mRNA levels and expression remained unchanged. No transcriptional activity and mRNA for other retinoid receptors were detectable. Both PAR-selective (TTNPB) and RXR-selective (3-methyl-TTNPB) agonists induced apoA-I synthesis at 1 and 10 uM. These results show that i) the slow increase in apoA-I secretion is caused by a slow increase of its mRNA level; ii) the apoA-I gene transcription in cynomolgus hepatocytes is induced rapidly by retinoids; iii) the added at-RA disappeared rapidly from the cultures, explaining the necessity for high initial concentrations; iv) RARalpha and/or RARbeta and RXRalpha are involved in the activation of apoA-I expression by retinoids. Chemicals/CAS: 4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid, 71441-28-6; alitretinoin, 5300-03-8; Apolipoprotein A-I; Benzoates; bexarotene; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; RNA, Messenger; Tetrahydronaphthalenes; Transcription Factors; Tretinoin, 302-79-4