Carbonic anhydrase isoenzymes

Carbonic anhydrase inhibitors decrease aqueous humor production by inhibition of the carbonic anhydrase isoenzyme II located in the ciliary body. In the eye, carbonic anhydrase catalyzes the conversion of water and carbon dioxide to bicarbonate and hydrogen ion, which is a significant step in aqueous humor production. Carbonic anhydrase inhibitors are available in systemic and topical preparations.10,13,14... 

Sly, W.S., Sato, S., and Zhu, X.L. (1991) Evaluation of Carbonic Anhydrase Isoenzymes in Disorders Involving Osteopetrosis and/or Renal Tubular Acidosis. Clinical Biochemistry 1, 311 318. 

Orally administered carbonic anhydrase inhibitors lower the intraocular pressure of glaucoma patients, however they induce a number of intolerable side effects associated with extraocular inhibition of the enzyme [5,6]. Thus, much research has been directed towards the search for a topically effective agent. Several compounds have been synthesized since the 1980 s in Merck Sharp Dohme Research Laboratories, and have been found to be topically active in man [7]. Unfortunately, many of these compounds were not very soluble. Attempts to obtain an active carbonic anhydrase inhibitor with good solubility resulted in the synthesis of Dorzolamide hydrochloride [8,9], which was first made available for pharmacological evaluation in 1987. Like other carbonic anhydrase inhibitors sulfonamides (such as acetazolamide, ethoxzolaniide, and methazolamide) dorzolamide is an inhibitor of human carbonic anhydrase isoenzymes I, II, and IV. In contrast to the other sulfonamides, dorzolamide is a potent inhibitor of isoenzymes II and IV, and a weak inhibitor of isoenzyme I [ 10]. Isoenzyme II is thought to play a major role in aqueous humor secretion. 

Carter, M. J. Carbonic anhydrase isoenzymes properties distribution and functional significance. BioL Rev. 47, 465 (1972)... 

Wistrand PJ, Schenholm M, Lonnerholm G (1986) Carbonic anhydrase isoenzymes CAI and CAII in the human eye. Invest Ophthalm Visual Sci 27 419-428... 

Leinonen J, Kivela J, Parkkila S, Parkkila AK, Rajaniemi H Salivary carbonic anhydrase isoenzyme VI is located in the human enamel pellicle. Caries Res 1999 33 185-190. 

Parkkila, S., Kaunisto, K., Kellokumpu, S., and Rajaniemi, H. (1991). A high activity carbonic anhydrase isoenzyme (CA II) is present in mammalian spermatozoa. Histochem. 95 477-482. 

Brinzolamide is a carbonic anhydrase inhibitor that causes an inhibition of carbonic anhydrase in the cihary processes of the eye deaeases aqueous. It is indicated in the treatment of elevated lOP inpatients with ocular hypertension or open-angle glaucoma. The development of topical carbonic anhydrase inhibitor took many years but was an important event because of the poor side-effect profile of oral carbonic anhydrase inhibitors (CAIs). Dorzolamide (Trusopt) and brinzola-mide both work by inhibiting carbonic anhydrase (isoenzyme n), which is found in the ciliary body epithehum. This reduces the formation of bicarbonate ions, which reduces fluid transport and thus lOP. hi fact, the P-receptor antagonist timolol has been combined with the carbonic anhydrase inhibitor dorzolamide in a single medication (Cosopt). 

The development of a topical carbonic anhydrase inhibitor was prompted by the poor side-effect profile of oral CAIs. Dorzolamide (trusopt) and brinzolamide (azopt) both work by inhibiting carbonic anhydrase (isoenzyme II), which is found in the ciliary body epithelium. This reduces the formation of bicarbonate ions, which reduces fluid transport and thus lOP. 

CAll[Mn] Manganese-substituted bovine carbonic anhydrase isoenzyme II... 

Dialysis of carbonic anhydrase against a zinc chelate, 2,6-pyridinedicarboxylate, removes the active-site zinc leaving apo-carbonic anhydrase (Scheme 1) [35-37]. In our experiments [38], dialysis of carbonic anhydrase from bovine erythrocytes (a mixture of isoenzymes) against 2,6-pyridinedicarboxylate in acetate buffer at pH 5.5 removed 90-95 mol% of the zinc as shown by inductively coupled plasma atomic emission spectrometry (ICP-AES). This amount is similar to that removed previously for bovine [35-37] and human [39] carbonic anhydrase. Consistent with this removal of the active-site zinc, the apo-carbonic anhydrase lost 93-97% of the original catalytic activity for the hydrolysis of p-nitrophenyl acetate. Similar treatment of bovine carbonic anhydrase isoenzyme II (available commercially) and human carbonic anhydrase isoenzyme II gave the corresponding apo-enzymes. 

Scheme 1 Dialysis of carbonic anhydrase against a zinc chelate (2,6-pyridinedicarboxylate) removed 90-95% of the active-site zinc. Subsequent dialysis against Mn(ll) yielded manganese-substituted carbonic anhydrase, CA[Mn]. Similar procedures yielded manganese-substituted carbonic anhydrase isoenzyme 11 (CAll[Mn]) and manganese-substituted human carbonic anhydrase isoenzyme II (hCAII[Mn])...

Topiramate-associated blue pseudo-chromhidrosis has been described [324 ]. Chromhidrosis is a rare skin disorder, in which the apocrine glands excrete sweat that contains lipofuscin pigments. Pseudo-chromhidrosis is a term used when the eccrine sweat is colored on the surface of the skin as a result of the deposit of extrinsic dyes or paints. Since some carbonic anhydrase isoenzymes are expressed in the sudoral eccrine glands, the hypothesized mechanism of this adverse effect was inhibition of this enzyme by topiramate. 

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