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PubMed1975

[The histochemical evidence of the cholinesterase in the integument by means of the copper ferro cyanide methode (author's transl)].

With the aid of the Ferrocyanidmethod from KARNOVSKI und ROOTS ChE-positiv structures in the skin of various laboratory animals and of man were located. Specific cholinesterase is found in verves, around apocrine sweat glands and around eccrine sweat glands of some species. In the stratum basale of the epidermis from the rat you can demonstrate a high concentration of acetylcholinesterase. Unspecific cholinesterase is detectable in nerves, in the blood vessels, in the lumen of apocrine sweat glands and sebaceous glands.

Acetylcholinesterase↗

PubMed1976

[The development of hair and the restoration of innervation in the skin transplants in man].

Various areas in 7 local flaps and in 6 free skin grafts from the back, abdomen and thigh, applied to the palm and fingers and retained for periods extending from several months to 17 years are studied. After the second year, the transplants display virtually complete recovery of the sensation for pain, touch, pressure and temperature. The hair roots in the transplants have varying thickness and reveal changes in the structure of the connective-tissue and outer epithelial sheath (Figs. 1, 2). The sebaceous glands are enlarged. Isolated sebaceous glands are encountered which do not communicate with the hair roots. In the upper layers of the corium bundles of myelin nerve fibers are observed, giving off small groups of 2-4 fibers each, with slightly ascending direction relative to the hair roots (Fig. 3). The nerve fibers break down into branches which are furthermore ramified into smaller branches, forming palisade-like endings along the outer epethelial sheath of the hair root (Figs. 4-8). They number 15-25, being usually thin, with a discrete number of thickenings, and resemble the normal fibers running along the hair roots of the donor site (Figs. 9, 10). No capsulated receptors, characteristic of the surrounding skin, are noted in the transplants. Hence, it is assumed that most likely, the endings of the regenerated nerve fibers along the hair roots, although uncapsulated and with identical structure, provide for perceiving the types of sensation, inherent of the hairy and glabrous human skin.

Female↗

PubMed1994

Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding sites in peripheral tissues of the rat: implications for receptor-mediated immune modulation by cannabinoids.

[3H]CP-55,940, a high-affinity cannabinoid receptor ligand, was used for in vitro binding and autoradiography in peripheral tissues in the rat. Specific cannabinoid receptor binding was found to be restricted to components of the immune system, i.e., spleen, lymph nodes and Peyer's patches. Displacement studies showed that this binding is identical (similar Kd and structure-activity profile) to that in brain. Cannabinoid receptors in the immune system are confined to B lymphocyte-enriched areas, i.e., the marginal zone of the spleen, cortex of the lymph nodes and nodular corona of Peyer's patches. Specific binding is absent in T lymphocyte-enriched areas, such as the thymus and periarteriolar lymphatic sheaths of the spleen. Certain macrophage-enriched areas, i.e., liver and lung, lack specific binding. Thus, the single peripheral cell type that may contain cannabinoid receptors is the B lymphocyte. Numerous sites have dense binding that could not be displaced by excess unlabeled drug. These nonspecific sites were found in the liver, adrenal glands and sebaceous glands, which are high in fat content, and in the heart, pancreas, components of the male and female reproductive systems and the epithelium of the esophagus. Thus, the highly lipophilic nature of cannabinoids does not appear to be the sole determinant of nonspecific binding. The data suggest that cannabinoids may exert specific receptor-mediated actions on the immune system of rats. Perhaps, also at high concentrations, cannabinoids exert membrane effects at sites where they are sequestered nonspecifically.

Adjuvants, Immunologic↗

PubMed1993

Immunohistochemical localization of paraquat in skin and eye of rat.

Immunohistochemical techniques were used to observe the localization of paraquat in the skin and eyes of rats. Paraquat poisoned rats were killed 3 h, 12 h, 24 h, 3 days, 7 days and 10 days after intravenous administration of paraquat. In skin, paraquat was localized in the ducts of sweat glands and sebaceous glands between 3 and 10 days after paraquat injection. In eyes, weak positive findings were observed in nerve fibers of retina between 3 and 10 days after the injection. In cornea, paraquat was localized in epithelial cells at the first 3 h and between 3 and 10 days after paraquat administration. Since skin occupies a vast area of the body in animals, as an organ, it seems to be an important storage pool for the redistribution of paraquat.

Animals↗

PubMed1997

Type I (RI) and type II (RII) receptors for transforming growth factor-beta isoforms are expressed subsequent to transforming growth factor-beta ligands during excisional wound repair.

Transforming growth factor (TGF)-beta isoforms (TGF-beta 1, -beta 2, and -beta 3) regulate cell growth and differentiation and have critical regulatory roles in the process of tissue repair and remodeling. Signal transduction for TGF-beta function is transmitted by a heteromeric complex of receptors consisting of two serine/threonine kinase transmembrane proteins (RI and RII). We have previously shown that each TGF-beta isoform is widely expressed in a distinct spatial and temporal pattern throughout the processes of excisional and incisional wound repair. As the presence of TGF-beta receptors determines cellular responsiveness, we have currently examined, by immunohistochemistry, the localization of RI (ALK-1, ALK-5) and RII throughout repair of full-thickness excisional wounds up to 21 days after wounding. The expression of RI (ALK-5) and RII co-localized in both the unwounded and wounded skin and was present in the same cell types as TGF-beta ligands. However, immunoreactivity for TGF-beta receptors, throughout repair, occurred 1 to 5 days later than TGF-beta isoform immunostaining. This implies that the presence of TGF-beta ligands may up-regulate TGF-beta receptors for function and/or may reflect a lag due to local processing of latent TGF-beta. As observed for the immunohistochemical localization of TGF-beta isoforms in unwounded skin, RI and RII were expressed throughout the four layers of the epidermis, showing a wavy pattern of slight to moderate immunostaining, and hair follicles, sweat glands, and sebaceous glands were moderately immunoreactive. The extracellular matrix, fibroblasts, and blood vessels in the dermis were not immunoreactive. After injury, as observed for TGF-beta ligands, RI and RII expression was increased in the epidermis adjacent to the wound and the epithelium migrating over the wound was completely devoid of TGF-beta receptor immunoreactivity until re-epithelialization was completed by day 7 after wounding. The dermis was only slightly immunoreactive for RI and RII until day 5 when, immediately under the wound, immunostaining for fibroblasts, connective tissue cells, and newly forming vasculature began to increase and remained intense until day 14. Consistent with the role for TGF-beta in scarring, numerous fibroblasts, ostensibly active in the production of extracellular matrix components, continued to be slightly immunoreactive for RI and RII at 21 days. The ALK-1 (TSR-1) type I receptor, which binds both activin and TGF-beta, showed slight immunostaining early in repair (days 1 to 7) that progressively became more intense later in repair after day 10 and through day 21. This suggests that there may be a switch to a different type I receptor, implying different functions for the ALK-1 and ALK-5 receptors. The concomitant expression of TGF-beta isoforms and their signal-transducing receptors denote potential spatial and temporal activity of TGF-beta. Thus, although TGF-beta ligand is present, TGF-beta would not function in wound repair until a later time when RI and RII appear. This information should aid in the development of receptor antagonists as a therapeutic approach to scarring and fibrosis. In addition, these studies underscore the importance of defining the expression of proteins in vivo to establish a basis for the analysis of mechanisms in vitro.

Animals↗

PubMed1999

NTP Toxicology and Carcinogenesis Studies of Oleic Acid Diethanolamine Condensate (CAS No. 93-83-4) in F344/N Rats and B6C3F1 Mice (Dermal Studies).

Oleic acid diethanolamine condensate is widely used as an emollient, thickener, and foam stabilizer present in cosmetic formulations of bath additives, shampoos, conditioners, lipsticks, and hair dyes. Male and female F344/N rats and B6C3F1 mice received dermal applications of diethanolamine in 95% ethanol for 13 weeks or 2 years. Genetic toxicology studies were performed in Salmonella typhimurium and L5178Y mouse lymphoma cells. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were admin istered 0, 25, 50, 100, 200, or 400 mg oleic acid diethanolamine condensate/kg body weight in ethanol dermally for 13 weeks. All male and female rats survived until the end of the study. The final mean body weights and body weight gains of 200 and 400 mg/kg males and the mean body weight gain of 400 mg/kg females were significantly less than those of the vehicle controls. The only chemical-related clinical finding was irritation of the skin at the site of application in most males administered 100 mg/kg or greater and in all females administered 50 mg/kg or greater. Segmented neutrophil counts were increased relative to the vehicle controls in the 400 mg/kg male group on days 5 and 19, in the 200 mg/kg female group on day 19 and at week 13, and in the 400 mg/kg female group on days 5 and 19 and at week 13. Alkaline phosphatase concentrations were significantly increased in the 200 mg/kg male group on day 19, the 200 mg/kg female group at week 13, and in the 400 mg/kg groups of males and females at week 13. Kidney weights of 200 and 400 mg/kg females were significantly greater than those of the vehicle controls. Lesions of the skin at the site of application included epidermal hyperplasia, parakeratosis, chronic active dermal inflammation, suppurative epidermal inflammation, and sebaceous gland hypertrophy in dosed rats. The severities of these lesions generally increased with increasing dose. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were admin istered 0, 50, 100, 200, 400, or 800 mg oleic acid diethanolamine condensate/kg body weight in ethanol dermally for 13 weeks. All male and female mice except one 800 mg/kg male survived until the end of the study. Final mean body weights and body weight gains of 800 mg/kg males and females and 400 mg/kg females were significantly less than those of the vehicle controls. Clinical findings in dosed mice included irritation of the skin at the site of application. Irritation occurred in all surviving dosed males and in most females administered 100 mg/kg or greater and progressed to ulcer in one 800 mg/kg male. The heart weights of 400 and 800 mg/kg males and females and 200 mg/kg females and the kidney weights of 50, 100, and 400 mg/kg males were significantly greater than those of the vehicle controls. Relative to the vehicle controls, the liver weights were increased in all dosed groups. Lesions of the skin at the site of application in dosed mice included epidermal hyperplasia, parakeratosis, suppurative epidermal inflammation, chronic active dermal inflammation, sebaceous gland hypertrophy, and ulcer. The severities of these lesions generally increased with increasing dose. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0, 50, or 100 mg oleic acid diethanolamine condensate/kg body weight in ethanol dermally for 2 years. Survival, Body Weights, and Clinical Findings: Survival of dosed male and female rats was similar to that of the vehicle control groups. Mean body weights of 100 mg/kg males were slightly less than those of the vehicle controls throughout most of the study. Mean body weights of 100 mg/kg females were less than those of the vehicle controls beginning at week 24. The only significant treatment-related clinical finding was mild to moderate irritation of the skin at the site of application in dosed males and females. Pathology Findings: The predominant effects of oleic acid diethanolamine condensate administration were minimal to moderate nonneoplastic lesions of the skin at the site of application in dosed rats. These lesioe lesions included epidermal hyperplasia, sebaceous gland hyperplasia, hyperkeratosis, parakeratosis, chronic active dermal inflammation, and ulcer. 2-YEAR STUDY IN MICE: Groups of 55 male and 55 female mice were administered 0, 15, or 30 mg oleic acid diethanolamine condensate/kg body weight in ethanol dermally for 2 years. Five animals from each group were evaluated at 3 months for gross lesions and skin histopathology. Survival, Body Weights, and Clinical Findings: Survival of dosed male and female mice was similar to that of the vehicle control groups. Mean body weights of dosed males and of 15 mg/kg females were similar to those of the vehicle controls throughout the study. Mean body weights of 30 mg/kg females were less than those of the vehicle controls from week 76 until the end of the study. The only significant treatment-related clinical finding was irritation of the skin at the site of application in 30 mg/kg males. Pathology Findings: The incidences of epidermal hyperplasia, sebaceous gland hyperplasia, and chronic active inflammation of the dermis in all dosed groups were significantly increased relative to the vehicle controls at 3 months and at 2 years. The increased incidences of hyperkeratosis in dosed males at 3 months and in dosed males and females at 2 years, of parakeratosis in 30 mg/kg males at 3 months and 2 years, and of ulcer in 30 mg/kg males and exudate in 30 mg/kg males and females at 2 years were also attributed to chem ical administration. GENETIC TOXICOLOGY: Oleic acid diethanolamine condensate was not mutagenic in S. typhimurium strain TA97, TA98, TA100, or TA1535, with or without S9 metabolic activation enzymes. In addition, it did not induce mutations in mouse L5178Y lymphoma cells treated with or without S9. CONCLUSIONS: Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of oleic acid diethanolamine condensate in male or female F344/N rats administered 50 or 100 mg/kg or in male or female B6C3F1 mice administered 15 or 30 mg/kg. Dermal administration of oleic acid diethanolamine condensate to male and female rats was associated with epidermal hyperplasia, sebaceous gland hyper plasia, hyperkeratosis, parakeratosis, chronic active inflammation of the dermis, and ulceration of the skin at the site of application. Dermal administration of oleic acid diethanolamine condensate to mice was associated with epidermal hyperplasia, sebaceous gland hyperplasia, hyperkeratosis, chronic active inflammation of the dermis, and exudate of the skin at the site of application in males and females and parakeratosis and ulcer of the skin at the site of application in males. Synonyms: Diethanolamine oleate; diethanolammonium oleate; (Z)-9-octadecenoic acid, compound with 2,2.-imnobis(ethanol) (1:1); oleamide diethanolamine

Journal Article↗

PubMed1987

Is increased 5 alpha-reductase activity a primary phenomenon in androgen-dependent skin disorders?

Testosterone metabolism was investigated in fractions of human skin, enriched in epidermis, dermis, sebaceous glands, and sweat glands, by histologic sectioning of skin punch biopsies, and the results were compared with two culturable skin cells, i.e., keratinocytes and fibroblasts. Since sebocytes could not be brought in culture, metabolism was also investigated in the hamster flank model. In the epidermal tissue of the skin biopsies the predominant metabolite was androstenedione, formed by the enzyme 17 beta-hydroxysteroid dehydrogenase. The same was true for cultured hair follicle keratinocytes. In the deeper skin layers the formation of androstenedione was markedly reduced, whereas the formation of 5 alpha-reduced metabolites was highly increased, with a maximum in the skin fractions containing large sebaceous glands. Cultured shoulder skin fibroblasts showed a markedly different testosterone metabolism compared with the sectioned skin biopsies, suggesting that dermal fibroblasts play a less important role in the overall skin testosterone metabolism. The present approach, allowing the comparison of testosterone metabolism in different substructures of the same skin biopsy provides new evidence that the high 5 alpha-reductase activity in the specific skin fractions must be mainly ascribed to the sebaceous glands. These results render a previous hypothesis, stating that the elevated level of 5 alpha-reductase and subsequent formation of dihydrotestosterone in androgenetic alopecia and acne (usually accompanied by seborrhea) could therefore simply be the consequence of sebaceous gland enlargement, much stronger. This hypothesis is further evaluated by quantitative correlation of sebaceous gland size with enzyme activity in the hamster flank model.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2001

Toxicology and carcinogenesis studies of coconut oil acid diethanolamine condensate (CAS No. 68603-42-9) in F344/N rats and B6C3F1 mice (dermal studies).

Coconut oil acid diethanolamine condensate, a mixture of fatty acid diethanolamides of the acids found in coconut oil, is widely used in cosmetics, shampoos, soaps, and related consumer products. Because of the lack of information about potential risks associated with long-term exposure, coconut oil acid diethanolamine condensate was selected as a representative of the diethanolamine chemical class for evaluation of toxicity and carcinogenic potential. Male and female F344/N rats and B6C3F1 mice received dermal applications of coconut oil acid diethanolamine condensate for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats received dermal applications of 0, 25, 50, 100, 200, or 400 mg coconut oil acid diethanolamine condensate/kg body weight in ethanol, five times per week for 14 weeks. All rats survived until the end of the study. Final mean body weights and body weight gains of 200 and 400 mg/kg males and females were significantly less than those of the vehicle controls. Clinical findings included irritation of the skin at the site of application in 100, 200, and 400 mg/kg males and females. Cholesterol concentrations were significantly decreased in 200 and 400 mg/kg males and in females administered 100 mg/kg or greater; triglyceride concentrations were also decreased in 200 and 400 mg/kg males. Histopathologic lesions of the skin at the site of application included epidermal hyperplasia, sebaceous gland hyperplasia, chronic active inflammation, parakeratosis, and ulcer. The incidences and severities of these skin lesions generally increased with increasing dose in males and females. The incidences of renal tubule regeneration in 100, 200, and 400 mg/kg females were significantly greater than the vehicle control incidence, and the severities in 200 and 400 mg/kg females were increased. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice received dermal applications of 0, 50, 100, 200, 400, or 800 mg coconut oil acid diethanolamine condensate/kg body weight in ethanol, five times per week for 14 weeks. All mice survived until the end of the study. Final mean body weights and body weight gains of dosed males and females were similar to those of the vehicle controls. The only treatment-related clinical finding was irritation of the skin at the site of application in males and females administered 800 mg/kg. Weights of the liver and kidney of 800 mg/kg males and females, the liver of 400 mg/kg females, and the lung of 800 mg/kg females were significantly increased compared to the vehicle controls. Epididymal spermatozoal concentration was significantly increased in 800 mg/kg males. Histopathologic lesions of the skin at the site of application included epidermal hyperplasia, sebaceous gland hyperplasia, chronic active inflammation, parakeratosis, and ulcer. The incidences and severities of these skin lesions generally increased with increasing dose in males and females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats received dermal applications of 0, 50, or 100 mg coconut oil acid diethanolamine condensate/kg body weight in ethanol five times a week for 104 weeks. Survival, BODY WEIGHTS, AND CLINICAL FINDINGS: The survival rates of treated male and female rats were similar to those of the vehicle controls. The mean body weights of dosed males and females were similar to those of the vehicle controls throughout most of the study. The only chemical-related clinical finding was irritation of the skin at the site of application in 100 mg/kg females. PATHOLOGY FINDINGS: There were marginal increases in the incidences of renal tubule adenoma or carcinoma (combined) in 50 mg/kg females. The severity of nephropathy increased with increasing dose in female rats. Nonneoplastic lesions of the skin at the site of application included epidermal hyperplasia, sebaceous gland hyperplasia, parakeratosis, and hyperkeratosis, and the incidences and severities of these lesions increased with increasing dose. The incidences of chronic active inflammation, epithelial hyperplasia, and epithelial ulcer of the forestomach increased with dose in female rats, and the increases were significant in the 100 mg/kg group. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice received dermal applications of 0, 100, or 200 mg coconut oil acid diethanolamine condensate/kg body weight in ethanol five times a week for 104 to 105 weeks. SURVIVAL, BODY WEIGHTS, AND CLINICAL FINDINGS: Survival of dosed male and female mice was generally similar to that of the vehicle controls. Mean body weights of 100 mg/kg females from week 93 and 200 mg/kg females from week 77 were less than those of the vehicle controls. The only clinical finding attributed to treatment was irritation of the skin at the site of application in males administered 200 mg/kg. PATHOLOGY FINDINGS: The incidences of hepatic neoplasms (hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma) were significantly increased in male and/or female mice. Most of the incidences exceeded the historical control ranges. The incidences of eosinophilic foci in dosed groups of male mice were increased relative to that in the vehicle controls. The incidences of renal tubule adenoma and renal tubule adenoma or carcinoma (combined) were significantly increased in 200 mg/kg males. Several nonneoplastic lesions of the skin at the site of application were considered treatment related. Incidences of epidermal hyperplasia, sebaceous gland hyperplasia, and hyperkeratosis were greater in all dosed groups of males and females than in the vehicle controls. The incidences of ulcer in 200 mg/kg males and inflammation and parakeratosis in 200 mg/kg females were greater than those in the vehicle controls. The incidences of thyroid gland follicular cell hyperplasia in all dosed groups of males and females were significantly greater than those in the vehicle control groups. GENETIC TOXICOLOGY: Coconut oil acid diethanolamine condensate did not show genotoxic activity in vitro. It was not mutagenic in Salmonella typhimurium, nor did it produce an increase in mutant L5178Y mouse lymphoma cell colonies. In addition, no increases in the frequencies of sister chromatid exchanges or chromosomal aberrations were observed in Chinese hamster ovary cells after incubation with coconut oil acid diethanolamine condensate. All these in vitro assays were conducted with and without induced S9 activation enzymes. In contrast to the uniformly negative results in vitro, positive results were obtained in a peripheral blood micronucleus test in male and female mice from the 14-week dermal study. CONCLUSIONS: Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of coconut oil acid diethanolamine condensate in male F344/N rats administered 50 or 100 mg/kg. There was equivocal evidence of carcinogenic activity in female F344/N rats based on a marginal increase in the incidences of renal tubule neoplasms. There was clear evidence of carcinogenic activity in male B6C3F1 mice based on increased incidences of hepatic and renal tubule neoplasms and in female B6C3F1 mice based on increased incidences of hepatic neoplasms. These increases were associated with the concentration of free diethanolamine present as a contaminant in the diethanolamine condensate. Exposure of rats to coconut oil acid diethanolamine condensate by dermal application in ethanol for 2 years resulted in epidermal hyperplasia, sebaceous gland hyperplasia, hyperkeratosis, and parakeratosis in males and females and ulcer in females at the site of application. There were increases in the incidences of chronic inflammation, epithelial hyperplasia, and epithelial ulcer in the forestomach of female rats. The severities of nephropathy in dosed female rats were increased. Exposure of mice to coconut oil acid diethanolamine condensate by dermal application for 2 years resulted in increased incidences of eosinophilic foci of the liver in males. Increased incidences of epidermal hyperplasia, sebaceous gland hyperplasia, and hyperkeratosis in males and females, ulcer in males, and parakeratosis and inflammation in females at the site of application and of follicular cell hyperplasia in the thyroid gland of males and females were chemical related.

Administration, Topical↗

PubMed1993

The androgen control of sebum production. Studies of subjects with dihydrotestosterone deficiency and complete androgen insensitivity.

To evaluate the androgen control of sebum, subjects with complete androgen insensitivity and male pseudohermaphrodites with inherited 5 alpha-reductase deficiency and decreased dihydrotestosterone (DHT) production had sebum production studied. A hydrophobic polymeric film applied to the forehead was used to measure sebum production through the use of air filled micropores. Sebum scores of normal preadrenarchal children (ages 2-6), and normal age-matched adult males and females, were studied as well as males treated with the 5 alpha-reductase inhibitor, finasteride, for benign prostatic hyperplasia who were studied at baseline and after drug therapy. Androgen insensitive subjects had no sebum production by this methodology, and the results were identical to preadrenarchal children. In contrast, adult male pseudohermaphrodites with 5 alpha-reductase deficiency and a selective decrease in DHT production had sebum production scores identical to normal age-matched males. Males with benign prostatic hyperplasia treated with the 5 alpha-reductase inhibitor, finasteride, to lower DHT levels did not decrease the sebum score from baseline values. The lack of demonstrable sebum in androgen-insensitive subjects clearly demonstrates the absolute androgen control of sebum production. The DHT dependency of the sebaceous gland, however, could not be demonstrated in this study. Two 5 alpha-reductase isoenzymes 1 and 2, have been described. 5 alpha-reductase-2 is the gene responsible for inherited 5 alpha-reductase deficiency. Although the degree of inhibition of DHT in utero and in adulthood in male pseudohermaphrodites with a defect in 5 alpha-reductase-2 enzyme activity caused severe impairment of external genital and prostate differentiation and decreased facial and body hair, it had no demonstrable effect on sebaceous gland development or function. Furthermore, lowering DHT levels in adulthood had no effect on sebum production. If the gland is rich in the enzyme 5 alpha-reductase-2, it is proposed that the sebaceous gland is either exquisitely sensitive to DHT, requiring only small amounts for normal development and function, or that male levels of testosterone compensate for DHT and maintain normal sebaceous gland activity throughout life. It is also possible that 5 alpha-reductase-1 is the enzyme of the sebaceous gland and is unaffected in the inherited condition and by finasteride.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2005

Expression of perilipin A on the surface of lipid droplets increases along with the differentiation of hamster sebocytes in vivo and in vitro.

To clarify the involvement of perilipin, a lipid-droplet-surface protein associated with adipocytes and steroidogenic cells, in the differentiation of sebocytes, we investigated the expression of perilipin in sebaceous glands in vivo and in vitro. Perilipin was expressed in sebaceous glands of the hamster auricle in vivo and was localized at the surface of intracellular lipid droplets in differentiated hamster sebocytes in vitro. Western blot analysis showed that perilipin with a molecular weight of approximately 57 kDa, which was identical to that in differentiated mouse 3T3-L1 adipocytes, was detected in cultured sebocytes, indicating that sebaceous glands expressed perilipin A. In addition, the production of perilipin A in cultured sebocytes was transcriptionally augmented by sebocytic-lipogenesis stimulators, insulin, and 5alpha-dihydrotestosterone, whereas it was decreased by a suppressor of sebocytic differentiation, epidermal growth factor. Furthermore, hamster sebocytes were found to express peroxisome proliferation-activating receptor alpha and gamma1, the activation of which by WY14643 and troglitazone, respectively, caused the transcriptional augmentation of perilipin A expression along with an increase in levels of triacylglycerols in lipid droplets in sebocytes. Therefore, these results provide novel evidence that the expression of perilipin A increases on the surface of intracellular lipid droplets augmented along with the differentiation of hamster sebocytes.

3T3-L1 Cells↗

PubMed1983

Sebaceous metaplasia of rat oral epithelium during chemical carcinogenesis.

Application of the carcinogen 4-nitroquinoline N-oxide (4NQO) thrice weekly to rat oral mucosa led to development of free sebaceous glands in 91% of all carcinogen-treated animals. The palatal epithelium was the area of predilection. The entire process from the transformation of single basal cells to the formation of the multi-alveoli sebaceous glands could be followed in detail. Solvent-treated animals demonstrated only a few sebaceous glands in the gingiva of the maxillary first molars whereas control animals seemed devoid of these structures. It is suggested that de novo formation of free oral sebaceous glands is caused by a metaplastic process due to local irritants among which the carcinogen 4NQO seems particularly powerful. A correlation between sebaceous metaplasia and carcinogenesis could be demonstrated.

4-Nitroquinoline-1-oxide↗

PubMed1989

T antigen expression and tumorigenesis in transgenic mice containing a mouse major urinary protein/SV40 T antigen hybrid gene.

A hybrid mouse major urinary protein (MUP)/SV40 T antigen gene was microinjected into fertilized mouse embryos and the resulting transgenic mice analyzed for the regulated expression of the transgene. Available evidence indicates that the MUP gene used for the hybrid gene construct is expressed in both male and female liver and possibly mammary gland. Three different transgenic lines exhibited a consistent pattern of tissue specific expression of the transgene. As a consequence of transgene expression and T antigen synthesis in the liver, both male and female transgenic animals developed liver hyperplasia and tumors. Transgene expression and liver hyperplasia commenced at approximately 2-4 weeks of age, the same time that MUP gene expression is first detected in the liver. The expression of the transgene resulted in an immediate strong suppression of liver MUP mRNA levels but had relatively little effect on other liver specific mRNAs. From 4 to 8 weeks, the liver increased several fold in size, relative to non-transgenic littermates. Definitive tumor nodules were not apparent until 8-10 weeks. The transgene was also consistently found to be expressed in the skin sebaceous glands and the preputial gland, a modified sebaceous gland. The expression of the transgene in the skin sebaceous glands is consistent with the presence of MUP mRNA in the skin and a putative role for MUPs in the transport and excretion of small molecules. Occasional expression of the transgene in other tissues (kidney and mammary connective tissues) was also noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2001

Expression, candidate gene, and population studies of the melanocortin 5 receptor.

In mouse the melanocortin 5 receptor is known to regulate sebaceous gland function. To clarify its role in man, we have studied melanocortin 5 receptor expression in skin, and allelic variation at the melanocortin 5 receptor locus in diverse human populations and candidate disease groups. Melanocortin 5 receptor protein and mRNA expression were studied by immunohistochemistry and reverse transcriptase polymerase chain reaction. Melanocortin 5 receptor mRNA was detected in normal skin and cultured keratinocytes but not in cultured fibroblasts or melanocytes. Immunohistochemistry revealed melanocortin 5 receptor immunoreactivity in the epithelium and appendages, including the sebaceous gland, eccrine glands, and apocrine glands, as well as low level expression in the interfollciular epidermis. In order to screen for genetic diversity in the melanocortin 5 receptor that might be useful for allelic association studies we sequenced the entire melanocortin 5 receptor coding region in a range of human populations. One nonsynonymous change (Phe209Leu) and four synonymous changes (Ala81Ala, Asp108Asp, Ser125Ser, and Thr248Thr) were identified. Similar results were found in each of the populations except for the Inuit in which only the Asp108Asp variant was seen. The apparent "global distribution" of melanocortin 5 receptor variants may indicate that they are old in evolutionary terms. Variation of melanocortin 5 receptor was examined in patients with acne (n = 21), hidradenitis supprativa (n = 4), and sebaceous gland lesions comprising sebaceous nevi, adenomas, and hyperplasia (n = 13). No additional mutations were found. In order to determine the functional status of the Phe209Leu change, increase in cAMP in response to stimulation with alpha-melanocyte-stimulating hormone was measured in HEK-293 cells transfected with either wild-type or the Phe209Leu variant. The variant melanocortin 5 receptor was shown to act in a concentration-dependent manner, which did not differ from that of wild type. We have therefore found no evidence of a causative role for melanocortin 5 receptor in sebaceous gland dysfunction, and in the absence of any association between variation at the locus and disease group, the pathophysiologic role of the melanocortin 5 receptor in man requires further study.

Acne Vulgaris↗

PubMed1982

Actions of isotretinoin and etretinate on the pilosebaceous unit.

Isotretinoin administered subcutaneously to male hamsters results in marked involution of the sebaceous glands of the flank organ without discernible effort on the other androgen-dependent structures, pigmented hair follicles, and dermal melanocytes. Treatment of androgen-stimulated female hamsters with isotretinoin prevented the androgen-induced growth of the sebaceous glands but not the formation of large pigmented hairs and dermal pigment cells. Etretinate, in comparable dosage, did not show the inhibitor effect on sebaceous gland growth. The hamster flank organ seems a promising system for assessment of the sebaceous gland inhibitory activity of retinoids and may be predictive for therapeutic activity in acne.

Animals↗

PubMed1982

Acne: endocrinologic aspects.

Acne is dependent for its development on several factors, one of which is hormonal. The principal and possibly sole mechanistic link between hormones and acne is sebum, the secretory product of the sebaceous glands which is highly androgen-sensitive. Some but not all, patients with acne can be shown to have systemic androgen abnormalities. In addition, there is evidence to suggest that androgens are metabolized abnormally in the skin, possibly resulting in excessive sebaceous gland secretion. Systemic endocrine therapy of acne is designed to reduce the androgenic stimulation of the sebaceous gland. Such treatment includes the peroral cyclic administration of estrogen for ovarian inhibition and the use of low-dosage glucocorticoid for adrenocortical androgen suppression. Combined estrogen-glucocorticoid treatment induces the most telling effect in reducing sebaceous gland activity.

Acne Vulgaris↗

PubMed2002

Cutaneous androgen metabolism: basic research and clinical perspectives.

The skin, especially the pilosebaceous unit composed of sebaceous glands and hair follicles, can synthesize androgens de novo from cholesterol or by locally converting circulating weaker androgens to more potent ones. As in other classical steroidogenic organs, the same six major enzyme systems are involved in cutaneous androgen metabolism, namely steroid sulfatase, 3beta-hydroxy-steroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, steroid 5alpha-reductase, 3alpha-hydroxysteroid dehydrogenase, and aromatase. Steroid sulfatase, together with P450 side chain cleavage enzyme and P450 17-hydroxylase, was found to reside in the cytoplasm of sebocytes and keratinocytes. Strong steroid sulfatase immunoreactivity was observed in the lesional skin but not in unaffected skin of acne patients. 3beta-hydroxysteroid dehydrogenase has been mainly immunolocalized to sebaceous glands, with the type 1 being the key cutaneous isoenzyme. The type 2 17beta-hydroxysteroid dehydrogenase isoenzyme predominates in sebaceous glands and exhibits greater reductive activity in glands from facial areas compared with acne nonprone areas. In hair follicles, 17beta-hydroxysteroid dehydrogenase was identified mainly in outer root sheath cells. The type 1 5alpha-reductase mainly occurs in the sebaceous glands, whereby the type II isoenzyme seems to be localized in the hair follicles. 3alpha-hydroxysteroid dehydrogenase converts dihydrotestosterone to 3alpha-androstanediol, and the use of 3alpha-androstanediol glucuronide serum level to reflect the hyperandrogenic state in hirsute women may be a reliable parameter, especially for idiopathic hirsutism. In acne patients it is still controversial if 3alpha-androstanediol glucuronide or androsterone glucuronide could serve as suitable serum markers for measuring androgenicity. Aromatase, localized to sebaceous glands and to both outer as well as inner root sheath cells of anagen terminal hair follicles, may play a "detoxifying" role by removing excess androgens. Pharmacologic development of more potent specific isoenzyme antagonists may lead to better clinical treatment or even prevention of androgen-dependent dermatoses.

Androgens↗

PubMed1987

Epitestosterone: a potential new antiandrogen.

Epitestosterone (EpiT) is the 17 alpha-hydroxy epimer of testosterone (T) and a natural steroid metabolite. It has previously been shown to be a 5 alpha-reductase inhibitor. We have studied EpiT as an antiandrogen using the hamster flank organ model. One-centimeter silastic capsules of crystalline T or dihydrotestosterone (DHT) were implanted subcutaneously in female Golden Syrian hamsters to provide continuous androgenic stimulation. After 3 weeks, the pigmented spot was measured and the flank organs were fixed for histologic sectioning. The maximum surface area (SA) from a central section of the sebaceous gland and the diameter of hair follicles were measured using a computerized digitizing tablet. Following T and DHT, respectively, there was a significant increase in pigmented spot size (656/382%), sebaceous gland SA (210/315%), and mean hair follicle diameter (80/56%). A 1-cm capsule of EpiT alone had no androgenic effect. Five- and ten-fold doses of EpiT were implanted with T or DHT. Epitestosterone significantly inhibited the T-dependent stimulation of pigment, sebaceous gland, and hair follicle at either 5- and/or 10-fold excess doses. Additionally, a 10-fold dose of EpiT also inhibited DHT-dependent stimulation of all 3 cutaneous structures. We conclude that EpiT was effective as an antiandrogen and had no intrinsic androgenic activity in the hamster flank organ. It probably functions both as a competitive inhibitor of the androgen receptor and as a 5 alpha-reductase inhibitor. Pigment and sebaceous gland growth were more sensitive than the hair follicle to androgen inhibition by EpiT at the time and doses tested.

Androgen Antagonists↗

PubMed2005

Congenital melanotic macules and Sebaceous Choristoma arising on the tongue of a newborn: epidermal choristoma?

Oral hyperpigmentation is a common event in older individuals, however, is exceptional in neonates (congenital melanotic macules). Conversely, 70-80% of people have sebaceous glands in the oral mucosa, with the tongue representing an ectopic location and termed sebaceous choristoma by some authors. We report a case that fulfills both conditions in a tongue lesion. A 1-month-old boy presented with a pigmented macula on his tongue noted at birth. An excisional biopsy was performed showing a lesion lined by an epidermal-like epithelium with basal pigmentation, under which, sebaceous glands, abortive hair follicles and ductal structures mimicking apocrine glands were found. Seven cases of congenital melanotic macules of the tongue have been reported, however, none of them showed sebaceous glands under the lesion. Furthermore, there has not been a reported case of sebaceous choristoma of the tongue present at birth. We present a case that shares clinical and histological features of both conditions and propose the name 'epidermal choristoma'.

Choristoma↗