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Biomedical subjects

A Vahlquist

Publications and source records attributed to A Vahlquist.

At least 73 records · Page 4Linked to original sources
PubMed1990

Vitamin A esterification in human epidermis: a relation to keratinocyte differentiation.

Keratinocytes from three different layers of epidermis (stratum basale, stratum spinosum, and stratum granulosum/corneum) were shown by high-performance liquid chromatography to contain retinol, 3,4-didehydroretinol and several fatty acyl esters thereof. The concentration of unesterified congeners increased 1.8-2.8 times from the inner to the outer layers of epidermis, while the corresponding increase in fatty acyl esters was 4.0-6.5 times. Together the esters represented 71% of the total vitamin A content in stratum granulosum/corneum as compared to 54% in stratum basale. The in situ synthesis of fatty acyl esters of retinol and 3,4-didehydroretinol (vitamin A2) was studied by addition of [3H]retinol to organ-cultured human breast skin. The radioactive compounds appearing in the epidermis after 48 h were, in order of abundance, retinyl esters, retinol, 3,4-didehydroretinyl esters, and 3,4-didehydroretinol. Studies at the subcellular level demonstrated the highest esterifying activity in the microsomal fraction. The enzyme catalyzing the reaction, acyl CoA:retinol acyltransferase (ARAT; EC 2.3.1.76), had a pH optimum of 5.5-6.0, which differs from that of ARAT in other tissues. ARAT activities in microsomes from different layers of epidermis were similar, but, owing to a presumed pH gradient in upper epidermis, the in vivo esterification of vitamin A may be enhanced in terminally differentiating keratinocytes. The mean ARAT activities in basal cell carcinomas and squamous cell carcinomas were less than 50% of the control values, and the relative amounts of retinyl esters were significantly lower than normal. We suggest that the esterification of vitamin A may also be of importance in relation to pathologic keratinocyte differentiation.

Acyltransferases↗
PubMed1990

Isotretinoin treatment of severe acne affects the endogenous concentration of vitamin A in sebaceous glands.

An investigation of pooled skin samples from 22 acne patients has shown that isotretinoin and its major metabolite, 4-oxo-isotretinoin, can be detected in sebaceous glands during treatment with isotretinoin (1 mg/kg/d for 4 months). The levels are less than those in the epidermis, thus excluding selective drug distribution as a prime explanation for drug function. Oral isotretinoin markedly increases retinol levels and decreases dehydroretinol levels in the skin while on therapy. The effect is more pronounced in sebaceous glands than in epidermis and dermis. The increased retinol levels probably reflect a metabolic interference with endogenous vitamin A, since isotretinoin cannot be converted into retinol in vivo. Previous studies have shown that dehydroretinol accumulates in hyperproliferative, keratinizing skin lesions and so its reduction with isotretinoin therapy may relate to a reduction in cell proliferation or to dedifferentiation. However, the precise interrelationships of these observations need further elucidation.

Acne Vulgaris↗
PubMed1990

UV-induced isomerization of oral retinoids in vitro and in vivo in hairless mice.

Ultraviolet (UV) irradiation causes isomerization and destruction of many vitamin A analogues (retinoids). Using high-performance liquid chromatography (HPLC), we investigated in vitro and in vivo the effects of UV irradiation on 2 all-trans aromatic retinoids (etretinate and acitretin) and on 13-cis retinoic acid (isotretinoin). When etretinate and acitretin dissolved in ethanol were irradiated with UVB (280-320 nm; 10-336 mJ/cm2) or UVA (320-400 nm; 1-5 J/cm2), extensive and reproducible cis-isomerizations occurred at the 13-position (cis/trans ratio approximately 1.6 in all experiments) but there was no progressive photodegradation of the molecules. Irradiation of isotretinoin produced only moderate trans-isomerization but the sum of HPLC peak heights fell with increasing UV doses, being 72% of the original value after 336 mJ/cm2 of UVB. Hairless mice were given etretinate (50 mg/kg bw), acitretin (200 mg/kg) or isotretinoin (50 mg/kg) on days 1, 4 and 7 and were irradiated daily for 8 d with 13 mJ/cm2 UVB plus 1 J/cm2 UVA. Samples of serum, dorsal skin and liver were collected and retinoids analyzed by HPLC. In the etretinate and acitretin-treated, irradiated animals the serum concentrations of the 13-cis isomers were 2-6 times higher than in nonirradiated controls. Irradiated epidermis also contained significantly higher concentrations of 13-cis etretinate and 13-cis acitretin than did control epidermis. The serum and epidermal concentrations of all-trans etretinate and acitretin were unchanged or even increased after irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acitretin↗
PubMed1990

Metabolism of very low density lipoproteins in rats with isotretinoin (13-cis retinoic acid)-induced hyperlipidemia.

A significant rise in plasma triacylglycerols from the control level of 0.89 mmol/l to 1.88 mmol/l (P less than 0.001) was observed in male Sprague-Dawley rats treated for 11 days with isotretinoin (oral dosing; 10 mg/day). This rise was due to an increased level of plasma very low density lipoproteins (VLDL). When VLDL from untreated rats were labeled with 125I-labeled tyramine-cellobiose and injected intravenously into rats treated for 10 days with isotretinoin (n = 6) and in control rats (n = 6), it was found that the disappearance of radioactivity from the blood was dramatically retarded in the treated animals. The disappearance could be divided into two phases, a rapid (alpha) phase dominated the first 5 min and was followed by a slower (beta) phase. The half-life of the beta-phase increased significantly from 53 +/- 7 min in the controls, to 120 +/- 62 min after isotretinoin. VLDL prepared from isotretinoin-treated animals (n = 6) had about the same half-life in control animals (62 +/- 8 min) as had ordinary VLDL. The elimination of tracer from the blood was mainly due to uptake by the liver. The amount of radioactivity in the liver after 30 min of circulation was significantly reduced from 34 +/- 7% of injected dose in controls to 24 +/- 5% in the isotretinoin group (P = 0.013). The uptake in other organs was less than 3% per organ and was essentially unaffected by the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Decreased retinyl ester concentrations in UV-induced murine squamous cell carcinomas.

Squamous cell carcinomas were induced in hairless mice by repeated irradiations with UVB (280-320 nm, total dose 30 J/cm2) plus UVA (320-400 nm, total dose 168 J/cm2). The irradiated animals and non-irradiated controls were fed on diets with or without vitamin A supplementation (20,000 IU/kg). At the appearance of tumours, 30 to 43 weeks after the last irradiation, the vitamin A (retinol plus retinyl ester) concentrations in the serum, liver, epidermis and tumours and the retinol esterifying activities in microsomes from epidermis and tumours were measured. The liver and epidermal vitamin A concentrations were 2-3 times higher in vitamin A supplemented than in unsupplemented animals, but did not differ between tumour-bearing animals and non-irradiated controls receiving identical diets. The vitamin A concentration in the tumours was significantly lower than in perilesional epidermis. The largest difference (p less than 0.001) between the tumour and epidermal values was observed in the vitamin A supplemented group. The low vitamin A content of the tumours was entirely due to a marked (2 to 6-fold) reduction in the retinyl ester fraction. In contrast, the retinol content of the tumours was increased to twice that of normal epidermis. The activity of the esterifying enzyme, acyl-CoA:retinol acyltransferase (EC 2.3.1.76), was unchanged. The reason for the reduced retinyl ester concentration thus remains unclear. Still, it is possible that a disturbed interconversion of retinol to retinyl esters plays a role in murine photo-carcinogenesis.

Acyltransferases↗
PubMed1988

Identification of 3-dehydroretinol (vitamin A2) in mouse liver.

3-Dehydroretinol (vitamin A2) and its long-chain fatty acyl esters have been isolated from hairless mouse liver by high-performance liquid chromatography (HPLC). In adult animals, these compounds amount to 1-2 micrograms/g liver, corresponding to 1-2% of the retinol (vitamin A1) concentration. Studies on the regulation of 3-dehydroretinol levels in liver showed that the age and vitamin A status of the animal affect the levels, but the relative proportions of retinol and 3-dehydroretinol are constant.

Age Factors↗
PubMed1988

UV irradiation and topical vitamin A modulate retinol esterification in hairless mouse epidermis.

The formation of fatty acyl esters of retinol, the major form of vitamin A in epidermis, is catalysed by microsomal enzymes. To study the regulation of retinol esterification, we exposed hairless mice to ultraviolet (UV) irradiation which destroys vitamin A and to topical retinol treatment. Vitamin A (retinol and retinyl esters) in serum and epidermis was analysed by high-performance liquid chromatography at 0-12 days after a single irradiation with UVB (280-320 nm; 0.34 J/cm2) or UVA (320-400 nm; 1.0 J/cm2). The immediate vitamin A reducing effects of UVB and UVA were similar, but UVB elicited a more rapid replenishment of epidermal vitamin A with a corresponding transient depletion of serum retinol after 2-3 days. The activity of retinyl ester synthetase, measured by an in vitro radiochemical assay, was unaffected by the irradiations. By contrast, the acyl-CoA:retinol acyltransferase (ARAT; EC 2.3.1.76) activity increased to 167% on the 2nd day after UVB-irradiation and to 124% after topical retinol, but was otherwise quite constant. The UVB- and retinol-induced ARAT activity was less dependent on exogenous palmitoyl-CoA than that of control microsomes and experiments indicated that this might be due to an increased endogenous concentration of long-chain acyl-CoA in the microsomes. We conclude that extreme variations in the vitamin A supply to epidermis, such as a rapid influx of unesterified retinol, may modulate the epidermal ARAT activity.

Acyltransferases↗
PubMed1987

Age-related variations in acyl-CoA:retinol acyltransferase activity and vitamin A concentration in the liver and epidermis of hairless mice.

Since the factors regulating retinol esterification by acyl-CoA:retinol acyltransferase are poorly understood, we studied the age-related variations in acyl-CoA:retinol acyltransferase activity in hairless mice. Epidermis and liver were collected at intervals from birth to adolescence (0-6 weeks). Vitamin A was analyzed by high-performance liquid chromatography and acyl-CoA:retinol acyltransferase by an in vitro radioincubation assay of microsomes. Epidermal vitamin A (retinol plus retinyl esters) increased 8-10 times after birth and by the age of 3 weeks adult values were attained. This increase was accompanied by a 2-fold increase in acyl-CoA:retinol acyltransferase activity in the epidermis between 3 days and 6 weeks of age. In young animals the dependence of acyl-CoA:retinol acyltransferase on exogenous co-substrate (palmitoyl-CoA) was also lower than in adult animals. Although a pronounced age-related accumulation of retinol was recorded in the liver, the activity of acyl-CoA:retinol acyltransferase did not increase with age and there was no change in the dependence of acyl-CoA:retinol acyltransferase on exogenous palmitoyl-CoA.

Acyltransferases↗
PubMed1987

Retinol esterification by mouse epidermal microsomes: evidence for acyl-CoA:retinol acyltransferase activity.

In an attempt to characterize the enzyme(s) responsible for retinol esterification in hairless mouse epidermis, various subcellular fractions were incubated with [3H]retinol and the reaction products (retinyl esters) isolated by high-performance liquid chromatography. The microsomal fraction exhibited the highest esterifying activity and was stimulated by the addition of palmitoyl-CoA and dithiothreitol, but not by palmitic acid. Saturation kinetics with an apparent Km of about 6 microM for retinol were noted. Experiments with competitive and noncompetitive inhibitors of [3H]retinol esterification established that the epidermal enzyme was an acyl-CoA:retinol acyltransferase (ARAT; EC 2.3.1.76). The specificity for retinol was not absolute; a few closely related vitamin A alcohols were equally good substrates. The ARAT activity was not significantly altered by physiologic variations in the epidermal vitamin A content. In conclusion, mouse epidermis expresses ARAT activity which may be of importance for the regulation of vitamin A metabolism at the cellular level.

Acyltransferases↗
PubMed1987

Clinical pharmacology of 3 generations of retinoids.

The bioavailability, plasma transport and tissue distribution of various retinoids are largely determined by their physicochemical properties; some are extremely lipidsoluble whereas others are relatively hydrophilic. Isotretinoin, a 1st generation retinoid, lacks the problematic affinity for fat. Etretinate, a 2nd generation aromatic retinoid, has been shown to accumulate in both fat tissues and in the adrenals. Etretin, the main free-acid metabolite of etretinate, is less lipophilic and is presently being tested as an alternative drug. Arotinoid ethyl ester, a 3rd generation aromatic retinoid which has as yet only undergone limited trials, is extremely potent making pharmacological evaluation difficult. The search for more potent retinoids has not so far resulted in a complete resolution of the efficacy and toxicity of the drugs.

Animals↗
PubMed1987

Etretinate pharmacokinetics in chronic renal failure. A preliminary study in psoriasis patients.

Chronic renal failure (CRF) interferes with the catabolism of retinol and is frequently associated with hypervitaminosis A. The effect of CRF on the plasma levels of etretinate (Tigason, Tegison), an aromatic retinoid, was therefore studied in 4 patients who were given the drug as part of a maintenance antipsoriatic regimen. The concentrations of the parent compound and its main metabolites (etretin and isoetretin) were monitored for 24 h after receiving a routine dose of the drug. In comparison with 4 non-CRF patients receiving similar maintenance doses of etretinate, although the CRF patients had higher peak levels of the parent compound (p less than 0.01), the levels of the metabolites were similar or lower. The plasma half-lives for all compounds were approximately the same in each group, indicating that the catabolism of the drug was not affected by CRF. However, elevated etretinate concentrations may increase the drug accumulation in fat tissues and thereby prolong the time required for final elimination of the drug.

Acitretin↗
PubMed1987

Vitamin A and beta-carotene concentrations at different depths of the epidermis: a preliminary study in the cow snout.

Vitamin A (retinol) is an anti-keratinizing agent essential for normal epithelial differentiation. In order to examine the epidermal distribution of vitamin A and provitamin A (beta-carotene), we took advantage of the extraordinarily thick snout epidermis of the cow which can be cut horizontally into at least 6 layers, representing keratinocytes at different stages of maturation. Extracts of saponified samples were analyzed for retinol and beta-carotene by reversed phase high-performance liquid chromatography. The highest retinol concentration (0.8 micrograms/g protein; n = 3) was recorded closest to the dermis; progressively decreasing amounts of retinol were found in the upper parts of epidermis. Maximum values of beta-carotene (1.0 micrograms/g; n = 7) were found in the lower parts of epidermis; substantially lower levels were seen at the dermal transition zone and in the upper parts of epidermis. The results suggest that the endogenous concentration of vitamin A in snout epidermis is inversely related to the degree of cellular differentiation.

Animals↗
PubMed1987

Plasma fat elimination tissue lipoprotein lipase activity and plasma fatty acid composition during sequential treatment with etretinate and isotretinoin.

In an attempt to elucidate the mechanisms underlying retinoid-induced hyperlipidemia, the effects of etretinate (Tigason) and isotretinoin (Roaccutane) on two different plasma fat elimination variables and on the plasma fatty acid composition were studied. Twelve patients with various hyperkeratotic disorders participated in a double-blind cross-over study of etretinate and isotretinoin. Each drug was given for 8 weeks with an 8-week intermission. On five occasions an intravenous fat tolerance test (IVFTT) was performed and the lipoprotein lipase activity (LPLA) in adipose tissue and skeletal muscle was measured. Isotretinoin significantly reduced the fat elimination rate as measured by IVFTT (p less than 0.001) and also decreased the muscle LPLA (p less than 0.05). The etretinate-induced depression of these variables was not statistically significant. The LPLA of adipose tissue and the plasma fatty acid composition were not markedly altered by any of the drugs. The observed changes are probably not sufficient to entirely explain retinoid-induced hyperlipidemia but the results strengthen the opinion that plasma lipid metabolism is more unfavourably affected by isotretinoin than etretinate.

Adipose Tissue↗