Metabolic barrier, skin

The skin not only is a barrier to restrict diffusion of chemicals into the body, it is also an organ that can metabolize a variety of topically applied substances before they become systemically available. The skin has many of the same enzymes as the liver. The activities of several cutaneous enzymes in whole skin homogenates have been measured and compared to hepatic activity in the mouse. The activities of the enzymes in the whole skin homogenates were typically 2-6% of the hepatic values. However, there is evidence that the enzymes are present primarily in the epidermis. Because the epidermis makes up only 2-3% of the total skin, the real activities may range from 80% to 240% of those in the liver. Enzyme systems present include a qrtochrome P-450 system and a mixed-function oxidase system. 

Desert rodents lead the most water-independent life of all vertebrates. Kangaroo rats can so reduce their evaporation that they are able to maintain water balance on only metabolic water. Other species survive on only meiabolic water plus free water in air-dry seeds. Respiratory water loss is reduced by cool nasal mucosal surfaces, which condense water from warm air coming from the lungs, before it can be expired. Skin impermeability involves a physical vapor barrier in the epidermis, pins unknown physiological factors. 

Vibrational microspectroscopy provides a unique means for molecular level structure characterization of a variety of biological processes associated with skin. For the past several years, this laboratory has utilized Raman and IR spectroscopy, microscopy, and imaging to monitor the biophysics of the skin barrier, mechanisms of drug permeation and metabolism in intact tissue, and, more recently, the complex events that transpire during wound healing in an ex vivo skin model [1-6]. 

There are several genetic skin diseases with known defects in the lipid metabolism. Atopic dermatitis, lamellar ichthyosis, and psoriasis have been the most widely studied with respect to epidermal barrier function and alterations in the lipid profile. Deviations in the lipid profile have been linked with an impaired stratum corneum barrier function. Atopic dermatitis is characterized by inflammatory, dry and easily irritable skin, and overall reduced ceramide levels in the stratum corneum [58-60]. In particular a significant decrease in the ceramide 1 level is observed, whereas the levels of oleate that is esterified to ceramide 1 are elevated [59]. Both aberrations may be responsible for the reduced order of the lamellar phases as observed with freeze fracture electron microscopy [61]. It has further been established that, in comparison to healthy stratum corneum, the fraction of lipids forming a hexagonal packing is increased [61]. A recent study reveals that the level of free fatty acids... 

The barrier properties of human skin have long been an area of multidisciplinary research. Skin is one of the most difficult biological barriers to penetrate and traverse, primarily due to the presence of the stratum corneum. The stratum cor-neum is composed of comeocytes laid in a brick-and-mortar arrangement with layers of lipid. The corneocytes are partially dehydrated, anuclear, metabolically active cells completely filled with bundles of keratin with a thick and insoluble envelope replacing the cell membrane [29]. The primary lipids in the stratum corneum are ceramides, free sterols, free fatty acids and triglycerides [30], which form lamellar lipid sheets between the corneocytes. These unique structural features of the stratum comeum provide an excellent barrier to the penetration of most molecules, particularly large, hydrophilic molecules such as ASOs. 

Although the stratum corneum acts as a simple physical barrier to outside influences, skin tissue as a whole is very active. It is crucial in maintaining the body s homeostasis, its essential steady-state environment. Skin maintains temperature and balance of electrolytes, the dissolved salts in internal body fluids. It is metabolically active and participates in hormonal and immune regulatory processes. More than serving as a passive barrier, it is proactive in response to xenobiotic insults and can be damaged in the defensive process by developing rashes and other symptoms. 

As described previously, one can induce dry, scaly skin, which shows features very similar to dermatitis such as atopic dermatitis and psoriasis. Use of this experimentally induced dry skin should enable the discovery of a new clinical methodology to cure or care for skin problems. Recently, several excellent in vitro skin models have been reported. Although they are also very useful models for the study of cutaneous metabolism, their function and microstructure are still different from those of intact skin. On the other hand, the mechanisms underlying abnormal desquamation, that is, scaling in the dry skin such as atopic dermatitis, are not completely known. Sato et al. reported55 the inhibition of protease in the SC induced scale without affecting epidermal mitosis. This result seems to be no direct relationship between skin surface appearance and epidermal proliferation. However, decline of SC barrier function induced epidermal hyperplasia, as described earlier.30 The loss of water content from SC also induced epidermal DNA synthesis.30 Further mechanistic studies on each of the dry skin features are required. 

In order to maintain water effectively within the skin the epidermis undergoes a process of maturation or terminal differentiation to produce a thin, metabolically inert, barrier, the SC. This heterogeneous structure has been likened to a brick wall in which the anucleated nonviable cells, termed corneocytes are represented as bricks embedded in a continuous matrix of specialized intercellular lipids (mortar).2 Each individual corneocyte can be viewed simplistically as a highly insoluble... 

The EFA metabolism is presented in several extensive reviews.9 16 17 Much of the information concerning EFA physiology and biochemistry has been derived from work in hepatocytes and may be of limited relevance to epidermis since a major role of the liver is to convert dietary lipids into energy stores. Meanwhile, keratinocytes are involved in the fatty acid metabolism required both for normal cellular processes and the specialized role in the permeability barrier. Unlike the liver, the epidermis does not possess the capacity to desaturate at the A5 or A6 position, and therefore the skin relies on a supply of AA, LA, and ALA from the bloodstream. There is evidence for a distinct fatty acid binding protein in keratinocyte plasma membranes that is involved in EFA uptake into the skin and also recycling of free fatty acids from the stratum corneum.18 The transport mechanism in epidermis differs from that in hepatocytes since there is preferential uptake of LA over OA, which may function to ensure adequate capture of LA for barrier lipid synthesis.18... 

Subcellular localization studies have identified P-450-dependent monooxygenase activity in adult hairless mice sebaceous glands. Phase II conjugation pathways have also been identified in skin. Extracellular enzymes including esterases are present in skin, which has been utilized to formulate lipid-soluble ester prodrugs which penetrate the stratum corneum and then are cleaved to release active drug into the systemic circulation. Finally, co-administration of enzyme inducers and inhibitors modulate cutaneous biotransformation and thus alter the systemic toxicity profile. These metabolic interactions that occur in skin have attracted a great deal of research attention and clearly illustrate that skin is more than a passive barrier to toxin absorption. 

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