Dysfunctional enzymes

Another class of therapeutic agents is used for the treatment of certain genetic diseases or other enzymatic disorders caused by the dysfunction or absence of one particular enzyme. This often leads to an unwanted accumulation or imbalance of metaboUtes in the organism. Eor example, some anticonvulsive agents are inhibitors for y-aminobutyric acid aminotransferase [9037-67-6]. An imbalance of two neurotransmitters, glutamate and y-aminobutyric acid, is responsible for the symptoms. Inhibition of the enzyme leads to an increase of its substrate y-aminobutyric acid, decreasing the imbalance and subsequently relieving the symptoms of the disease. 

Cadmium is extremely toxic and accumulates in humans mainly in the kidneys and liver prolonged intake, even of very small amounts, leads to dysfunction of the kidneys. It acts by binding to the —SH group of cysteine residues in proteins and so inhibits SH enzymes. It can also inhibit the action of zinc enzymes by displacing the zinc. 

Until recently, the cardiotonics and a diuretic were the treatment of choice for HE However, other dragp such as the angiotensin-converting enzyme (ACE) inhibitors, and beta blockers have become the treatment of choice during the last several years. See Figure 39-1 for an example of a method of determining treatment for left ventricular systolic dysfunction. See Chapters 23, 42, and 46 for more information on the beta blockers, ACE inhibitors, and diuretics, respectively. 

Smith, C.D., Carney, J.M., Starke-Reed, P.E., Oliver, C.N., Stadtman, E.R., Floyd, R.A. and Markesberg, W.R, (1991). Excess brain protein oxidation and enzyme dysfunction in normal < ing and in Alzheimer s disease. Proc. Natl Acad. Sci. USA 88, 10540-10543. 

Oxidation of enzyme sulphydryl groups by free radicals (Armstrong and Buchanan, 1978) and by the longer lived chloroamines (Weiss et al., 1983), contributes to enzymic dysfunction and to the decrease in serum sulphydryl levels, primarily mercaptoalbumin, found in coalworkers with rheumatoid inflammatory disease (Thomas and Evans, 1975). Formation of the S-nitroso adduct of plasma mercaptalbumin is thought to provide a metastable reservoir for intravascular nitric oxide release (Stamler etal., 1992). 

Chymostatin-sensitive Il-generating enzyme Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction Trial Collaborative Study Captopril Trial ( The Effect of Angiotensin-Converting Enzyme Inhibition on Diabetic Nephropathy ) calcium channel blocking agents Candesartan in Heart Failure Assessment of Reduction in Morbidity and Mortality Trial congestive heart failure, but the latest recommendations use HF for heart failure chronic kidney disease cardiac output... 

To control risk factors and prevent major adverse cardiac events, statin therapy should be considered in all patients with ischemic heart disease, particularly in those with elevated low-density lipoprotein cholesterol. In the absence of contraindications, angiotensin-converting enzyme inhibitors should be considered in ischemic heart disease patients who also have diabetes melli-tus, left ventricular dysfunction, history of myocardial infarction, or any combination of these. Angiotensin receptor blockers... 

Testosterone also plays a significant albeit complex role in erectile function. Testosterone is responsible for much of a man s libido. With low serum concentrations, libido declines. Additionally, testosterone helps with stabilization of intracavernosal levels of nitric oxide synthase, the enzyme responsible for triggering the nitric oxide cascade. Interestingly, some patients with low or borderline low serum concentrations of testosterone will have normal erectile function, while some with normal levels will have dysfunction. 

Hereditary deficiency of phosphoglycerate kinase (PGK) is associated with hereditary hemolytic anemia and often with central nervous system dysfunction and/or myopathy. The first case, reported by Kraus et al. (K24), is a heterozygous female, and the results are not so clear. The second family, reported by Valentine et al. (V3), is a large Chinese family, whose pedigree study indicates that PGK deficiency is compatible with X-linked inheritance. To date, 22 families have been reported (04, T25, Y3). Nine of these have manifested both symptoms five have shown only hemolysis seven have shown the central nervous system dysfunction and/or myopathy but without hemolysis and one case, PGK Munchen, is without clinical symptoms (F5). PGK II is an electrophoretic variant found in New Guinea populations (Y2). Red blood cell enzyme activity, specific activity, and the kinetic properties of this polymorphic variant are normal. 

Recently, it has been shown that inhalation of MWNTs caused suppression of the systemic immunity without resulting in significant lung inflammation or tissue damage [82,83]. Inhaled MWNTs in fact modified the functionality of spleen cells in exposed mice [82]. Notably, the activity of cyclooxygenase (COX) enzymes in spleen was affected as a response to a cytokine (TGF(5) released from the lungs. This cytokine activated the COX pathway in the spleen, triggering T-cell dysfunction and systemic immunosuppression [83]. 

Butler R, Morris AD, Burchell B, Struthers AD. DD angiotensin-converting enzyme gene polymorphism is associated with endothelial dysfunction in normal humans. Hypertension 1999 33 1164-1168. 

Exner DV, Dries DL, Domanski MJ, Cohn JN. Lesser response to angioten-sion-converting enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl... 

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