At present, not all the cytoplasmic and membrane-associated CA isozymes have been comprehensively identified in the human skin, even though the availability of specific antibodies and CAIs has helped considerably (Briggman et al. 1983; Noda et al. 1986, 1987; Mukarami et al. 1987; Nagao et al. 1993; Fujikawa-Adachi et al. 1999; Ivanov et al. 2001). However, little is known regarding the physiological consequences of their activation or inhibition on the metabolic processes within human skin cells. Based on the assumption that knowledge of the various cell types containing an abundance of the enzyme will contribute to the understanding of its biological significance and on the specific distribution pattern described previously, it is possible speculatively to advance an interesting and questionable view on the biological significance of these findings. In this view, it can be easily suggested that both isozymes I and II expressed in the cytoplasm and the basolateral membranes of the epithelial cells of the suprabasal and basal layers (where CA IX is negative) might potentially be involved in physiological cell proliferation and adhesion. Studies by Nogradi (1998) seemed to retract this theory, revealing no clear relationship of CAs I and II with tumorigenesis. In contrast to CA I and II expression, CA IX is not expressed in normal human skin (Ivanov et al. 2001), suggesting that it is not apparently implicated in physiological epithelial cell growth regulation and proliferation. Studies by Liao et al. (1994) have shown a distinct expression of CA IX protein in cervical displasia and carcinoma. This suggests that CA IX expression is more restricted to cell growth, thus strengthening the attractive hypothesis of its role in neoplastic cell proliferation, and, possibly, in malignant transformation (Liao et al. 1994; Saarnio et al. 1998a, 1998b; Vermylen et al. 1999). However, its function in reactive, hyperplastic processes as well as intercellular interactions and cell adhesions in different organs other than the skin cannot be completely ruled out (Pas-torekova et al. 1997; McKiernan et al. 1997; Turner et al. 1997).
CA-positive epidermal cells generally fall into the class of cells engaged in transport of fluid and ions, but the positive immunohistochemical observation of isozymes I and II in the inner layer of endothelial cells of the capillaries and sweat glands might be related to the complex phenomena of macromolecular secretion into luminal structures or bicarbonate and other ion exchanges as well documented by other investigators in eccrine sweat and large salivary glands (Briggman et al. 1983; Noda et al. 1986, 1987; Mukarami et al. 1987; Nagao et al. 1993; Fujikawa-Adachi et al. 1999; Ivanov et al. 2001; Spicer et al. 1982).
Models that receive particular attention in providing further evidence and helping explain the evolving concepts of CAs physiology are those that report the clinical effects and systemic adverse events from the use of CAIs. Such interesting pharmacological agents, sulfonamide CAIs, have a firm place in medicine and are mainly useful as diuretics or to treat and prevent a variety of diseases such as glaucoma, epilepsy, congestive heart failure, mountain sickness, gastric and duodenal ulcers, neurological disorders and osteoporosis (Supuran and Scozzafava 2000a; Supuran et al. 2003). Cases of olygohydrosis, a potentially serious adverse event characterized by deficient production and secretion of sweat, were reported in six children treated with zonisamide, an antiepileptic drug chemically classified as a sulfonamide and first marketed in Japan in 1989 (Knudsen et al. 2003). The apparent increased risk of oligohydrosis in the pediatric age group might be related to the dose and resulting blood levels of zonisamide and its metabolites. The present understanding of the pathophysiology of drug-induced oligohydrosis in pediatric patients is limited. Diminished sudomotor responsiveness, hypohidrosis or oligohydrosis and heat and fever after 2 to 3 months of treatment have also been reported in patients treated with topiramate, another recently marketed antiepileptic drug that inhibits CA (Arcas et al. 2001). The cumulative researches on the CA present in the literature might provide clues to possible mechanisms. Zonisamide inhibition of CA could modify the acid-base (acid equivalents) and ionic (mainly Ca2+ availability) cellular environment of the eccrine sweat gland epithelial cells. The result would be a confor-mational change (alteration in membrane form) and a decrease in the responsiveness of eccrine sweat gland muscarinic receptors to cholinergic stimulation (Knudsen et al. 2003). The drug might, in part, mediate its effects by influencing pH dynamics, H+ concentration and available Ca2+ transient at the level of ion channels and receptors.
While investigating the effectiveness of the most commonly used drug (aceta-zolamide) at high altitude for prevention and therapy of acute mountain sickness, Burtscher and Likar (2002) suspected a relationship between the medication and the development of leukonykia of all fingernails following high-altitude exposure. The authors suggested that a severe hypoxia induced by a CAI was responsible for the nail changes.
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