Hepatic Cysteine Dioxygenase Activity Research Articles

The Effect of Dietary Cysteine Level on Cysteine Metabolism in Rats

Male, Sprague-Dawley rats were fed l-amino acid diets that contained 0.4% l methionine and either 0, 0.2% (control), or 2.6% l-cysteine (free base) for 5 or 20 days. Hepatic cysteine dioxygenase activity in rats fed 2.6% cysteine was 5 and 3-times as great as in pair-fed control rats at 5 and 20 days, respectively. Cysteine sulfinate decarboxylase activity in liver of rats fed 2.6% cysteine for 20 days was about 40% of the pair-fed control level. The activity of cysteine sulfinate aminotransferase and the rate of cysteine desulfhydration were not influenced by dietary cysteine content. Rats that had been fed these diets for 5 days were intubated with 5 g of diet that contained either 0.2% or 2.6% l-[35S]cysteine. The 24-hour urinary excretion of total 35S, 35SO4, and [35S]taurine by rats that had been fed 2.6% cysteine for 5 days and intubated with 0.2% l-[35S]cysteine was 1.4-, 1.8-, and 2.4-fold, respectively, that of pair-fed control rats. About 2.1, 1.8, and 9.1 times as much 35S, 35SO/4, and [35S]taurine, respectively, were excreted by rats fed 2.6% cysteine for 5 days and intubated with 2.6% l-[35S]cysteine as was excreted by pair-fed control rats. Urinary excretion of these metabolites was not different between rats fed 0 and 0.2% cysteine. These results indicate that the cysteine sulfinate pathway plays a major regulatory role in the metabolism of excess cysteine.cysteine cysteine desulfhydrase cysteine dioxygenase cysteine sulfinate decarboxylase taurine sulfate

Induction of Cysteine Dioxygenase Activity by Oral Administration of Cysteine Analogues to the Rat: Implications for Drug Efficacy and Safety

One of the major steps in the oxidation of the sulphur-containing amino acid, L-cysteine, is the production of cysteine sulphinic acid, catalysed by the enzyme cysteine dioxygenase. This enzyme plays a key role in the intermediary metabolism of sulphur-containing compounds. The activity of this crucial enzyme is known to be influenced by sulphur-compound intake, being increased in animals fed an excess of L-cysteine or methionine. However, the affects on this enzyme of the chronic administration of drugs similar in structure to cysteine are unknown. This has now been investigated using the anti-rheumatic agent, D-penicillamine, and the mucoactive compound, S-carboxymethyl-L-cysteine. Repeated oral administration of these sulphur-containing drugs to male Wistar rats for five consecutive days led to a significant increase in hepatic cysteine dioxygenase activity. This increase in the production rate of cysteine sulphinic acid remained evident until returning to control levels four days after cessation of drug administration. These observations provide evidence that these two drugs interact with the intermediary biochemistry of sulphur compounds and may provide hitherto unappreciated insights into mechanisms by which therapeutic effects and adverse reactions may occur.

Regulation of cysteine dioxygenase and γ-glutamylcysteine synthetase is associated with hepatic cysteine level

Two hepatic enzymes, cysteine dioxygenase (CDO) and γ-glutamylcysteine synthetase (GCS), play important regulatory roles in the response of cysteine metabolism to changes in dietary sulfur amino acid or protein levels. To examine the time-course of changes in CDO and GCS activities, CDO and GCS-catalytic or heavy subunit protein and mRNA levels, and cysteine and glutathione levels, we adapted rats to either a low protein (LP) or high protein (HP) diet, switched them to the opposite diet, and followed these parameters over 6 days. Hepatic CDO activity and amount, but not mRNA level, increased in response to higher protein intake; the t 1/2 of change for CDO activity or protein level was 22 h for rats switched from a LP to a HP diet and 8 h for rats switched from a HP to a LP diet, suggesting that the HP diet decreased turnover of CDO. Hepatic GCS activity, catalytic subunit amount and mRNA level decreased in response to a higher protein intake. GCS catalytic subunit level changed with a similar t 1/2 for both groups, but the change in GCS activity in rats switched from a LP diet to a HP diet was faster (∼16h) than for rats switched from a HP to a LP diet (∼74h). Hepatic cysteine and glutathione levels reached new steady states within 12 h (LP to HP) or 24 h (HP to LP). CDO activity appeared to be regulated at the level of protein, probably by diminished turnover of CDO in response to higher protein intake or cysteine level, whereas GCS activity appeared to be regulated both at the level of mRNA and activity state in response to the change in cysteine or protein availability. These findings support a role of cysteine concentration as a mediator of its own metabolism, favoring catabolism when cysteine is high and glutathione synthesis when cysteine is low.

Role of the liver in regulation of body cysteine and taurine levels: a brief review.

The first-pass metabolism of dietary sulfur amino acids by the liver and the robust upregulation of hepatic cysteine dioxygenase activity in response to an increase in dietary protein or sulfur amino acid level gives the liver a primary role in the removal of excess cysteine and in the synthesis of taurine. Hepatic taurine synthesis is largely restricted by the low availability of cysteinesulfinate as substrate for cysteinesulfinate decarboxylase, and taurine production is increased when cysteinesulfinate increases in response to an increase in the hepatic cysteine concentration and the associated increase in cysteine dioxygenase activity. The upregulation of cysteine dioxygenase in the presence of cysteine is a consequence of diminished ubiquitination of cysteine dioxygenase and a slower rate of degradation by the 26S proteasome.

Variations in Dietary Protein but Not in Dietary Fat Plus Cellulose or Carbohydrate Levels Affect Cysteine Metabolism in Rat Isolated Hepatocytes

To determine if previously observed effects of dietary protein on hepatic cysteine metabolism were due specifically to increases in dietary protein or to the accompanying decreases in dietary carbohydrate, two experiments were conducted. In one experiment, rats were fed diets that contained different levels of protein vs. an isocaloric mixture of fat + cellulose and a constant amount of carbohydrate. In the other, rats were fed diets that contained a constant amount of protein but different levels of carbohydrate vs. an isocaloric mixture of fat + cellulose. Diets were fed for 2–3 wk and hepatocytes were then isolated. Hepatic cysteine dioxygenase activity increased and cysteinesulfinate decarboxylase and γ-glutamylcysteine synthetase activities decreased in a stepwise manner when protein was added to the diet at the expense of fat + cellulose. Changes in cysteine dioxygenase, cysteinesulfinate decarboxylase and γ-glutamylcysteine synthetase activities were consistent with changes in rates of cysteine catabolism, taurine production and glutathione synthesis, respectively, by intact hepatocytes incubated with 0.2 mmol/L cysteine. When the carbohydrate to fat + cellulose ratio was varied, but the protein level was held constant, little or no change in enzyme activities or levels of metabolite production was observed. Regulation of the activities of enzymes involved in cysteine metabolism is predominantly due to changes in dietary protein intake and not to the associated changes in intake of other dietary macronutrients.

Influence of Dietary Protein Levels on Hepatic Cysteine Dioxygenase Activity in Rainbow Trout

Influence of Dietary Protein Levels on Hepatic Cysteine Dioxygenase Activity in Rainbow Trout

Hepatic Cysteine Dioxygenase Activity and Sulfur Amino Acid Metabolism in Rats: Possible Indicators in the Evaluation of Protein Quality

Experiments were carried out to examine the possibility that the sulfur amino acid metabolism of rats may be an indicator of the nutritional value of dietary protein. Rats were fed diets containing 8, 16 or 24% of gluten, soy protein or casein for 3 wk. Hepatic cysteine dioxygenase activity, hepatic concentration of glutathione, cysteine and taurine and urinary taurine were examined. In addition, the sulfur amino acid metabolism of rats fed these diets fortified with the appropriate first limiting amino acid for 7 d was also examined. High urinary taurine excretion was observed in the three gluten groups, whereas very low urinary taurine excretion was observed with up to 24% soy protein or up to 16% casein. The hepatic hepatic cysteine dioxygenase activities of the gluten diet groups were higher than those of corresponding soy protein or casein diet groups, except that of rats fed the 24% casein diet. The hepatic concentrations of both glutathione and cysteine in gluten diet groups were also higher than those of corresponding soy protein or casein diet groups, except 24% soy protein and 16 and 24% casein diet groups. In rats fed the casein or soy protein diets urinary taurine excretion and hepatic cysteine dioxygenase activity increased with increasing methionine supplementation, the first limiting amino acid. Conversely, in rats fed the gluten diet both urinary taurine excretion and hepatic cysteine dioxygenase activity decreased with increasing lysine supplementation, the first limiting amino acid. These findings suggest that urinary taurine excretion and hepatic cysteine dioxygenase activity may be useful as sensitive indicators of the nutritional value of dietary protein.

Response of the kitten to dietary taurine depletion: Effects on renal reabsorption, bile acid conjugation and activities of enzymes involved in taurine synthesis

1. 1. Kittens were adapted to a semipurified diet and then fed either a control diet that contained 0.1% taurine or a taurine-free diet for 6 weeks; at the end of the feeding period, kittens fed the taurine-free diet had plasma and liver taurine concentrations that were 0.38 and 0.15%, respectively, of those for control kittens. 2. 2. Hepatic cysteinesulfinate decarboxylase activity in taurine-deficient kittens was five-times the level in control kittens, but hepatic cysteine dioxygenase activity was not affected by the dietary treatment. 3. 3. Taurine-conjugated bile acids made up 98% of the total bile acids in the gall bladder of control kittens, but they accounted for only 44% of the total bile acids in the bile of taurine-depleted kittens; both the concentrations of taurine-conjugated bile acids and total bile acids were markedly decreased in taurine-deficient kittens. 4. 4. No effect of taurine depletion on the fractional excretion of taurine in the urine was observed. 5. 5. The kitten may have some mechanisms for adapting to a low-taurine diet, but these are clearly not sufficient to maintain tissue taurine levels in the absence of dietary taurine.

Metabolism of Cysteine, Cysteinesulfinate and Cysteinesulfonate in Rats Fed Adequate and Excess Levels of Sulfur-Containing Amino Acids

The oxidation of cysteine, cysteinesulfinate and cysteinesulfonate labeled with 14C in the 1- and 3-positions was studied in rats that had been fed diets with adequate or excess cysteine. Consumption of excess cysteine for 5 or 10 days resulted in an increase in hepatic cysteine dioxygenase activity and a decrease in hepatic cysteinesulfinate decarboxylase activity but had no effect on the oxidation of the C-1 or C-3 of cysteine, cysteinesulfinate or cysteinesulfonate. When the labeled compounds were administered by intraperitoneal injection, 41% of cysteine, 100% of cysteinesulfinate and 37% of cysteinesulfonate were oxidized over an 8-hour period. The percentage of the oxidized cysteine, cysteinesulfinate and cysteinesulfonate that was converted to taurine was calculated to be 83, 70 and 100%, respectively. When these same compounds were administered intragastrically, the relative flux to taurine was lower for all compounds; 41% of the oxidized cysteine, none of the cysteine-sulfinate and 11% of the oxidized cysteinesulfonate appeared to be converted to taurine. Metabolism of intragastrically administered cysteine may be more indicative of what happens to dietary cysteine, whereas metabolism of intraperitoneally administered cysteine and cysteinesulfinate may be more indicative of liver metabolism and of the metabolism of endogenous cysteine and cysteinesulfinate.

Decrease of Rat Liver Cysteine Dioxygenase (Cysteine Oxidase) Activity Mediated by Glucagon

The hepatic cysteine dioxygenase activity of rats was markedly decreased by the intraperitoneal administration of glucagon. The enzyme activity was also decreased by either dibutyryl cyclic AMP or theophylline. The prior administration of actinomycin D completely blocked the glucagon-mediated decrease of enzyme activity, while administrations of this inhibitor of protein synthesis after glucagon injection did not block the decrease of enzyme activity. A single administration of actinomycin D resulted in a slight increase of cysteine dioxygenase activity in the rat liver. On the other hand, the injection of cycloheximide resulted in a rapid decrease of the hepatic cysteine dioxygenase with a half-life of 2.5 h. The half-life of the enzyme in rat liver after glucagon administration was one hour. The administration of hydrocortisone or insulin had no effect on the glucagon-mediated decrease of cysteine dioxygenase of rat liver. The enzyme activity of alloxan diabetic rat liver was almost the same as that of the intact rat liver. The evidence obtained here suggests that enhancement of degradation or inactivation of cysteine dioxygenase is responsible for the glucagon-mediated decrease of the enzyme activity in rat liver.