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Biomedical subjects

A Vahlquist

Publications and source records attributed to A Vahlquist.

At least 55 records · Page 3Linked to original sources
PubMed1994

Biologic activities of retinoic acid and 3,4-didehydroretinoic acid in human keratinocytes are similar and correlate with receptor affinities and transactivation properties.

The biologic activities of retinoic acid and 3,4-didehydroretinoic acid, two endogenous vitamin A derivatives in various tissues, were compared to their affinities for the nuclear retinoic acid receptors and their ability to induce transcriptional activation. Both retinoids were equipotent inducers of differentiation of F9 teratocarcinoma cells. In a morphologic assay, using reconstructed skin, retinoic acid and 3,4-didehydroretinoic acid inhibited keratinization at a concentration of 100 nM. In cultured keratinocytes, a 50% inhibition of the production of the keratinocyte transglutaminase enzyme was achieved with about 20 nM for both retinoids. The in vitro binding to the nuclear retinoic acid receptors alpha, beta, and gamma showed that retinoic acid and 3,4-didehydroretinoic acid had almost equal affinities for the receptors with Kds ranging from 3 to 47 nM. The transcriptional activation resulting from the addition of the two retinoids to cells co-transfected with alpha, beta, or gamma retinoic acid receptor expression vectors and a retinoic acid responsive element linked to the chloramphenicol acetyltransferase reporter gene was similar. Finally, it was demonstrated that retinoic acid did not metabolize to 3,4-didehydroretinoic acid, and a slow conversion of 3,4-didehydroretinoic acid into retinoic acid was not sufficient to explain the biologic effects produced by the former compound. In conclusion, the present study demonstrates that retinoic acid and 3,4-didehydroretinoic acid have the same activity in several different test systems, but their metabolism differs depending on the cell type used.

Cells, Cultured↗
PubMed1994

Expression of cytosolic retinoid-binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts.

Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol-binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies, and in cultured epidermal keratinocytes and dermal fibroblasts. Transcripts for cellular retinol-binding protein (CRBP) I and cellular retinoic-acid-binding protein (CRABP) I were found in normal skin, keratinocytes, and fibroblasts. CRABP II transcripts were detected in skin and keratinocytes. A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin. mRNA transcripts for serum retinol-binding protein (s-RBP) were detected in all tissues and cells. The biological importance of s-RBP expression in keratinocytes and fibroblasts is not known, but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid, or in the retransportation of cellular retinoids into the extracellular space.

Base Sequence↗
PubMed1994

In vivo studies concerning a pH gradient in human stratum corneum and upper epidermis.

Human skin has an acid mantle of pH 4-6, contrasting with the almost neutral pH of the interior body and implying the existence of a pH gradient over the horny layer that might influence a variety of epidermal processes. In an attempt to characterize the pH gradient, we applied a glass electrode to the volar surface of the forearm before and after consecutive strippings with sello-tape. Before stripping, the surface pH (mean +/- SD) was 4.5 +/- 0.2 in men (n = 7) and 5.3 +/- 0.5 in women (n = 7), the values gradually increasing to pH 6.9 +/- 0.4 in men and 6.8 +/- 0.5 in women after about 100-120 tape strippings, which completely removed the stratum corneum. When plotted against the number of strippings, the pH values usually conformed to a sigmoid curve with inflection (50% change) after about 60 strippings, at a level corresponding histologically to the lower third of stratum corneum. Similar gradients were found also in skin of the abdomen and calf. Stripping with cyanoacrylate resin produced a similar gradient, even though this form of stripping was 10 times more effective. The healing process after tape stripping was studied by determining pH and transepidermal water loss in 5 persons over a period of 14 days. The importance of the re-established pH gradient is discussed in relation to the many pH-dependent enzymes operating in stratum corneum.

Adult↗
PubMed1993

Detection of mRNA transcripts for retinoic acid, vitamin D3, and thyroid hormone (c-erb-A) nuclear receptors in human skin using reverse transcription and polymerase chain reaction.

Differentiation of keratinocytes involves both non-genomic and genomic events. The genomic effects are regulated by ligand-dependent transcription factors, e.g. the steroid/thyroid super-family of nuclear receptors. In the present study we examined mRNA expression of receptors for retinoic acid, thyroid hormone, and vitamin D3 in normal human skin and cultured keratinocytes using reverse transcription coupled to the polymerase chain reaction. The vitamin D3 receptor and the retinoic acid receptor (RAR) gamma together with the more distantly related RXR alpha were amplified extensively in skin and cultured keratinocytes. RAR alpha was amplified at a lower level, and RAR beta was almost undetectable. The thyroid hormone receptors alpha 1 and beta 1 were weakly amplified, but to comparable levels. Because receptors for retinoic acid, thyroid hormones, and vitamin D3 are all expressed in human epidermis differentiation of keratinocytes is probably regulated at transcriptional level by these molecules. It remains to be seen whether alterations in the expression of the nuclear receptors occur in certain skin disorders.

Base Sequence↗
PubMed1992

Long-term safety of retinoid therapy.

The concern about long-term toxicity of oral synthetic retinoids has developed because many patients, especially those with genodermatoses, require lifelong therapy. Several organ systems are at risk, especially the hepatic, skeletal, and cardiovascular systems. Although acute hepatotoxicity is a rare side effect of etretinate and acitretin therapy, prospective studies have not demonstrated chronic liver toxicity. The frequency of bone changes induced by retinoids is difficult to estimate, because this adverse effect is usually asymptomatic and requires x-ray or scintigraphic examination for detection. Atherosclerosis develops in many patients who receive long-term retinoid therapy, but the extent to which the process is aggravated by drug-induced hyperlipidemia is not known. Many patients have now been treated with either etretinate or isotretinoin continuously for as many as 15 years and have not developed any signs of severe chronic toxicity. However, continued intense surveillance is recommended for patients expected to require lifelong therapy.

Cardiovascular System↗
PubMed1992

Expression of cellular retinoid-binding proteins during normal and abnormal epidermal differentiation.

Retinoids have important roles in growth and differentiation of epidermal cells. We have analyzed the expression of two intracellular retinoid-binding proteins, the cellular retinol-binding protein type I and the cellular retinoic acid-binding protein type I, during normal and abnormal epidermal differentiation. Both proteins were found to be expressed in normal epidermis with increasing expression from basal layer towards superficial layers. In psoriatic lesions, a hyperproliferative condition of the skin, the epidermal expression of cellular retinol-binding protein I was induced, whereas expression of cellular retinoic acid-binding protein I was sharply down-regulated. This and other features of psoriatic lesions indicate that down-regulation of cellular retinoic acid-binding protein I expression might cause aberrant retinoid-regulated gene expression in skin. In basal and squamous cell carcinomas, cellular retinoic acid-binding protein I expression was down-regulated, whereas cellular retinol-binding protein I was expressed. Apart from epidermal cells, a mesenchymal, dendritic cell-type, strongly expressing cellular retinoic acid-binding protein I, was identified in the dermis. In several hyperproliferative conditions of the skin, including psoriasis, and squamous and basal cell carcinomas, this cell type was abundant. These results have implications for the role of retinoids in normal and abnormal epidermal differentiation and suggest that part of the phenotype of psoriasis is due to inappropriate metabolism of retinoic acid in skin.

Adult↗
PubMed1992

Oral acitretin in psoriasis: drug and vitamin A concentrations in plasma, skin and adipose tissue.

The purpose of the present study was to determine the concentrations of acitretin and its main metabolite, 13-cis acitretin, in epidermis, subcutis and plasma in twelve psoriatic patients treated with 30 mg acitretin orally daily for 6 months. In addition, endogenous concentrations of vitamin A were monitored. Blood samples and biopsies from normal appearing skin were obtained prior to therapy, after 1 and 6 months of treatment and finally 1 month after cessation of therapy. Using a highly sensitive liquid chromatography method concentrations of synthetic retinoids and endogenous retinoid (retinol, 3,4-didehydroretinol) were analysed in hydrolyzed tissue samples and plasma. Steady-state concentration of acitretin in epidermis (17 +/- 9 ng/g) was reached within 1 month of therapy. There was a significant correlation between the individual plasma trough value and the epidermal concentration of acitretin after 1 month of therapy. The acitretin concentrations in subcutis varied from 15 to 1437 ng/g, but the mean values at 1 and 6 months of therapy were similar (177 and 227 ng/g, respectively). After stopping therapy the acitretin level was below the detection limit in both epidermis and serum within 1 month in 9 out of 12 patients. In contrast, only 3 of the patients were negative for acitretin in subcutis biopsies obtained 1 month after stopping therapy. The occurrence of a presumed tissue contaminator with characteristics similar to 13-cis acitretin prevented quantitation of this metabolite in many subcutis samples. The epidermal, subcutis and serum composition of retinol and 3,4-didehydroretinol remained unchanged during therapy, indicating no or only minimal interaction between acitretin and endogenous vitamin A metabolism.

Acitretin↗
PubMed1991

Retinol uptake and metabolism to 3,4-didehydroretinol in human keratinocytes at various stages of differentiation.

The concentration of 3,4-didehydroretinol, an epidermal metabolite of retinol, is changed both in association with keratinizing disorders and during treatment with certain synthetic retinoids. To delineate further the factors regulation biosynthesis of 3,4-didehydroretinol, keratinocytes from three different layers of normal epidermis were prepared by trypsinization and incubated with [3H]-retinol for 20 h. Cell-bound [3H]-retinol and 3,4-[3H]-didehydroretinol were separated by high-performance liquid chromatography. The results indicate that the uptake of retinol and the synthesis of 3,4-didehydroretinol occur predominantly in undifferentiated cells from the basal and spinous layers of the epidermis.

Cell Differentiation↗
PubMed1991

Synthetic retinoids affect differently the epidermal synthesis of 3,4-didehydroretinol.

For unknown reasons, the epidermal concentrations of retinol and its metabolite 3,4-didehydroretinol become characteristically changed during treatment with certain synthetic retinoids. In the present study we investigated [3H]retinol uptake and conversion to 3,4-[3H]didehydroretinol in cultured human skin exposed to six different retinoids. The tissue accumulation of [3H]retinol increased by 50-130% following addition of 1.3 microM of all-trans-retinoic acid, 13-cis-retinoic acid, or 3,4-didehydroretinoic acid (putative metabolites of retinol), and by 13-55% after addition of acitretin, arotenoid Ro 13-7410, or 4-(N-hydroxyphenyl)retinamide. The formation of 3,4-[3H]didehydroretinol was markedly inhibited (minus 80-90%) by the three putative retinol metabolites, moderately inhibited (minus 60-70%) by the aromatic retinoic acid analogues acitretin and arotinoid, and only slightly inhibited (minus 25%) by 4-(N-hydroxyphenyl)retinamide. Addition of citral and ketoconazole, substances known to interfere with the oxidative metabolism of vitamin A, diminished the formation of 3,4-didehydroretinol by 70 and 95%, respectively, but only marginally affected the retinol values. We conclude that the increase in retinol and marked reduction in 3,4-didehydroretinol concentrations in epidermis especially during treatment with 13-cis-retinoic acid are most likely due to diminished conversion of retinol to 3,4-didehydroretinol, but whether or not this reflects feedback inhibition of retinol metabolism or direct inhibition of a specific enzyme remains to be established. Nonetheless, in vitro analysis of 3,4-didehydroretinol biosynthesis appears to be a sensitive means for screening compounds for their ability to interfere with the cutaneous vitamin A metabolism.

Female↗
PubMed1990

Either chick embryo dermis or retinoid-treated mouse dermis can initiate glandular morphogenesis from mammalian epidermal tissue.

Excess retinoids can cause developing mouse vibrissa follicles to be transformed into mucous glands in organ culture. The objective was to test the hypothesis that retinoids act in this system by altering morphogenetic properties of the dermis. After inititation by retinoic acid (RA) in organ culture, glands were shown to develop further in embryonic skin grafted to the chick chorioallantoic membrane (CAM). Recombinants of 12.5 day mouse epidermis with untreated or RA-treated mouse or chick dermis were then grafted to CAM for 7 days. For homospecific recombinants, 13.5 day mouse dermis originated from 11.5 day skin cultured for 2 days, with or without 5.2 microgram/ml RA. For heterospecific recombinants, 12 day dermis came from chick embryos, previously injected with 250 microgram RA. Glands were absent from the homospecific recombinants including untreated mouse dermis, but appeared in 26% of those with RA-treated dermis. Among heterospecific recombinants, 75% of those with RA-treated chick dermis and 29% of those with untreated dermis had glands. Untreated 10-12 day chick skin contained two forms of endogenous vitamin A, retinol (4.5 microgram/g protein) and dehydroretinol (3.7 microgram/g protein), while 13-14 day mouse skin contained only retinol (1.8 microgram/g protein), as shown by high performance liquid chromatography. RA injection increased retinol and dehydroretinol in chick skin, while RA was undetectable. Thus RA can act through mouse dermis to form epithelial glands and through chick dermis to increase the incidence of glands. The glands in recombinants with untreated chick dermis may result from the higher levels of endogenous retinoids in chick skin, compared with mouse skin.

Allantois↗