Julius D. Militante

The role of taurine in the pathogenesis of the cardiomyopathy of insulin-dependent diabetes mellitus

The cellular and molecular physiology and pathology of insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) are mostly studied and understood through the use of animal models. Fundamental differences between the IDDM and NIDDM animal models may help to explain the etiology behind diabetic cardiomyopathy, one of the most severe complications of IDDM. Experimental rat models of IDDM exhibit a characteristic increase in tissue levels of taurine in the heart, a change that is not seen in NIDDM rats. This article deals with the causes and possible consequences of this observation which may contribute to the development of diabetic cardiomyopathy. Modulation of pyruvate dehydrogenase (lipoamide) (PDH; EC 1.2.4.1) activity was found to be a possible mode for taurine involvement. PDH is a mitochondrial protein and is the rate-limiting step in the generation of acetyl CoA from glycolysis. In IDDM, PDH activity is decreased through a mechanism that includes the stimulation of the de novo synthesis of a kinase activator protein (KAP) which phosphorylates PDH and inactivates the enzyme. This lesion does not occur in NIDDM rat hearts. Taurine is known to inhibit the phosphorylation of PDH in vitro, and in taurine-depleted rats PDH phosphorylation is known to increase. Thus, the increased levels of taurine in the diabetic heart may be inhibiting this phosphorylation which in turn may be stimulating the synthesis of KAP through a negative feedback process. The main argument for this theory would be the lack of change in both the taurine levels and the activity of PDH in the NIDDM rat model.

Dietary taurine supplementation: Hypolipidemic and antiatherogenic effects

Abstract Taurine supplementation may prove to be a safe and convenient method to reverse high blood cholesterol and the associated rise in atherosclerosis. Although human studies are limited, experiments using animal models provide extensive proof of the hypolipidemic and antiatherogenic effects of taurine. Examples of these animal models involve feeding with high-fat diets, genetically determined or heritable disease conditions, and artificially induced or genetic diabetes. Most importantly, the addition of taurine to the diet clearly has effects against pathological increases in serum and liver cholesterol and triglycerides. Another consistent and noteworthy effect of taurine is the simulation of cholesterol 7α-hydroxylase activity, the enzyme that is responsible for the catabolism of cholesterol into bile acids. Taurine also exhibited considerable effects on atherosclerotic lipid accumulation, perhaps through an antioxidative mechanism and through the elevation of HDL cholesterol levels. Data from animal model systems support the specific cardiovascular benefits of taurine, and hopefully, this research will be continued in human studies in the future.

Taurine uptake activity in the rat retina : protein kinase C-independent inhibition by chelerythrine

Taurine, a regulatory amino acid of various biochemical processes in the retina, requires an efficient uptake system to maintain the high physiological concentration of taurine in the retina. Taurine uptake was characterized in both whole retinal preparations and in isolated rod outer segments (ROS) in terms of uptake kinetics and possible protein kinase C (PKC)-dependent regulation. Two uptake systems, a high- and a low-affinity system, were found in whole retinal preparations while only the high-affinity system was found in the isolated ROS. All the uptake systems characterized were inhibited by guanidinoethane sulfonate (GES), a well-known competitive inhibitor of taurine uptake. Stimulation and inhibition of PKC activity with phorbol myristate acetate and with staurosporine, respectively, produced no significant effect on taurine uptake. On the other hand, chelerythrine (CHT), a documented potent PKC inhibitor, was found to cause significant inhibition of the two taurine uptake systems, presumably through a PKC-independent mechanism. The data demonstrate that CHT may be a useful tool in studying taurine uptake in the retina and specifically in the ROS.

Effect of taurine on chelerythrine inhibition of calcium uptake and ATPase activity in the rat retina

Taurine potentiates calcium uptake in whole retinal homogenates as well as in rod outer segments and mitochondrial fractions. The aim of this study was to correlate taurine potentiation of calcium uptake with its effects on other cellular processes through the use of chelerythrine (CHT), a modulator of protein kinase C (PKC), ATPase activity, and, as recently shown, of retinal protein phosphorylation. CHT inhibited calcium uptake only when ATP was present, and inhibition increased significantly in conditions of ATP excess. Taurine potentiated ATP-dependent calcium uptake but decreased the potency of ATP to induce uptake activity. CHT inhibition of calcium uptake exhibited similar potencies in the presence and absence of taurine, and this inhibition seemed to be independent of PKC inhibition. Because of the ATP-dependence of the observed effect, total ATPase activity was studied using similar treatments. In the absence of taurine, CHT inhibited ATPase activity with the same potency (IC50 approximately 59.3 microM) as with calcium uptake inhibition (IC50 approximately 87.9 microM), presenting a possible mechanism of action of CHT. In the presence of taurine, no such correlation was observed, suggesting an ATPase-independent mechanism of action. In fact, taurine did not potentiate ATPase activity, but rather it decreased the potency of CHT inhibition of ATPase, effects incongruent with the effects of taurine on calcium uptake and on CHT inhibition of calcium uptake. Enzyme kinetic experiments provided more supporting data. Taurine was found to cause an increase in the affinity of the ATP substrate for the ATPase enzyme, contradicting the aforementioned effect of taurine to decrease the potency of ATP to induce calcium uptake. Thus, taurine seems to increase calcium uptake through a hitherto unreported mechanism distinct from its modulation of ATPase activity.

Increased cardiac levels of taurine in cardiomyopathy: the paradoxical benefits of oral taurine treatment

Taurine is an amino acid found in high concentrations in mammalian tissues, however, its function has yet to be fully understood. Certain cellular processes are known to be modulated by taurine, e.g., calcium metabolism, protein phosphorylation, and osmoregulation. Taurine has been used with both experimental and clinical success in treating various cardiovascular diseases. Significantly, treatment with oral taurine has been beneficial in improving signs and symptoms of congestive heart failure. Taurine treatment is safe and inexpensive, and at the very least, taurine may be therapeutically useful as a nutritional supplement in patients with cardiovascular disease. Curiously, certain conditions or models of cardiovascular disease which benefit from taurine treatment exhibit increased levels of taurine in the heart. This article serves to review the various experimental and clinical models which have been used to study the paradoxical benefit of therapy with oral taurine.

Effects of short chain alkanols on the inducible nitric oxide synthase in a glial cell line

Ethanol inhibits inducible nitric oxide synthase (iNOS) expression in C6 glioma cells by an unknown mechanism. Because relatively high concentrations are needed for inhibition in drug‐naïve cells (IC50∼150 mM), suppression due to cytotoxicity is one possible mechanism that has not been ruled out. Therefore, the present study examined the effects of ethanol and other alkanols on C6 glioma cell viability and iNOS activity to better understand the mechanism for inhibition. iNOS expression was induced in cell culture with lipopolysaccharide and phorbol ester treatment. Nitrite accumulation in culture medium, the in vitro conversion of [3H]‐L‐arginine to [3H]‐L‐citrulline, and immunoblotting were used to quantify iNOS induction and activity. Trypan blue exclusion, extracellular release of lactate dehydrogenase, and quantity of total cell protein were used as measures of viability. Short chain alkanols, methanol through 1‐heptanol, concentration‐dependently inhibited nitrite accumulation. Longer chain alkanols, 1‐octanol and 1‐decanol, did not except at cytotoxic concentrations. Experiments indicated short chain alkanol inhibition was not due to direct actions on iNOS catalytic activity, but that it transpires during iNOS induction. Immunoblots showed reduced iNOS protein levels. Correlation analysis ruled out iNOS inhibition as being due to decreased cell number, total cell protein, or cell viability. In contrast, there was significant correlation with physical measures of lipophilicity. In conclusion, inhibition of iNOS expression by ethanol and other short chain alkanols is not due to cytotoxicity. Instead, the strong correlation with lipophilicity suggests the inhibition derives from an interaction with unknown hydrophobic cellular sites.

Effects of Taurine Supplementation on Cholesterol Levels with Potential Ramification in Atherosclerosis

It is quite convincing from the literature that taurine supplemented in the diet and administered to various animal models (rat, mouse, and rabbit) has a significant effect in reducing both total cholesterol and the induced atherogenic lesions. Unfortunately, there are very few studies in which taurine has been administered to humans. Because of the present prevalence of high fat diets in our society and the serious sequellae associated with high serum cholesterol levels, it is considered after reviewing the data in the literature that more studies are needed to access the value of supplemental dietary taurine in the human model. If truly beneficial in lowering human hypercholesterol levels, taurine could be an inexpensive, nontoxic dietary supplement with significant cardiovascular properties.

Taurine Stimulation of Calcium Uptake in the Retina

Taurine (2-aminoethanesulfonic acid) is a free amino acid found in high millimolar concentrations in animal tissues and various review articles and manuscripts have been written concerning its physiologic function1–3. Some suggested functions for taurine are related to neurotransmission, to osmoregulation and to protection against oxidative stress. Special attention has been paid to the mechanism of action of taurine in the retina, especially in the decades of the 70’s and 80’s, mainly because of experiments which suggest that taurine is most abundant in the retina compared to other tissue types and because of studies which linked taurine deficiency with visual dysfunction4. More importantly, the simple supplementation of the diet with taurine proved to be sufficient in alleviating the vision problem, theoretically through the replenishment of the depleted taurine levels.

Unique pharmacological interactions of taurine and chelerythrine in the retina.

The effects of taurine and chelerythrine (CHT) on ATP-dependent calcium uptake and the phosphorylation of the approximately 20 kDa phosphoprotein in the retina were compared. In the absence of the CHT, taurine stimulated ATP-dependent calcium uptake and attenuated the phosphorylation of the approximately 20 kDa phosphoprotein. On the other hand, CHT produced the opposite results in the absence of taurine. When the two agents were used simultaneously, it was found that CHT non-competitively inhibited the action of taurine to stimulate calcium uptake, while taurine non-competitively inhibited the action of CHT to stimulate the phosphorylation of the approximately 20 kDa phosphoprotein. The data present an unusual pharmacological mechanism for controlling the signal transduction pathway involving the two distinct cellular processes being studied. Given the unique data, a control system is proposed in which the function of the approximately 20 kDa phosphoprotein is linked to the stimulation of ATP-dependent calcium uptake.

The nature of taurine binding in the retina.

Lombardini and Prien1 reported on the kinetics of taurine binding to rat retinal membranes and outlined the basic methodology behind binding experiments. Like most binding studies, the binding of radiolabeled ligand was counted in the presence of varying concentrations of unlabeled ligand under conditions which favor binding over transport. These conditions include low incubation temperatures and denaturation of tissue samples, both of which inhibit, in theory, active transport. Binding kinetics were then calculated using non-linear regression analysis of the binding curves through the range of total ligand concentrations, or alternately, linear regression analysis of the Scatchard plots. Binding kinetics include the dissociation constant (Kd) which is the total ligand concentration that produces half-maximal binding, and the estimated maximal binding level (Bmax). These values are used to specifically characterize the binding of a particular ligand.