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Biomedical subjects

Z Gregus

Publications and source records attributed to Z Gregus.

At least 73 records · Page 4Linked to original sources
PubMed1980

Development and regression of the hepatic microsomal enzyme induction and stimulation of biliary excretion produced by phenobarbital in rats.

The time-course effect of a single dose (75 mg/kg i.p.) of phenobarbital (PB) and that of prolonged PB treatment (75 mg/kg daily i.p., for 1 to 5 days) on the hepatic excretory and microsomal enzyme functions have been studied in rats. PB given in a single dose resulted in hypercholeresis 6 hr, an increase in the biliary excretion rate of bromcresol green and in hepatic cytochrome P-45 concentration 12 hr, and shortening of hexobarbital sleeping time 24 hr after the administration. All these changes, except the hypercholeresis, became gradually more apparent following the repeated daily administration of PB. Regression of the changes was faster in biliary excretory function than in microsomal function. Biliary flow and biliary output of bromcresol green returned to the control level at 72 hr after a single dose of PB or at 5 days after the cessation of a 5-day PB treatment, whereas enzyme induction was still apparent at those times. These results indicate that no close correlation in time exists between PB produced hepatic microsomal enzyme induction and the stimulatory effect of PB on biliary excretion.

Animals↗
PubMed1980

Comparison of the effects of cholestyramine and aluminium hydroxide on the biliary bile acid excretion in rats. An experimental model for the depletion of bile acids in bile.

Bile flow and biliary excretion of dihydroxy- and trihydroxy-bile acids have been determined in control, cholestyramine (250--2000 mg/kg p.os)- and aluminium hydroxide (250--2000 mg/kg p.os)-pretreated rats. Cholestyramine proved to be a more potent bile acid depleting agent than aluminium hydroxide. The depressing effect of cholestyramine on bile flow was also more significant than that of aluminium hydroxide. Cholestyramine-pretreatment seemed to be a suitable experimental model for the depletion of bile acids in rat bile.

Aluminum Hydroxide↗
PubMed1980

Time course of the effects of phenobarbital on biliary flow and on the biliary excretion of bromcresol green in rats.

Biliary flow and the biliary excretion of bromcresol green were measured in rats injected i.p. with a single dose of phenobarbital, 75 mg/kg. Biliary flow began to increase 6 h after the injection, it reached a peak at 36 h and returned to the control level at 72 h. In the same rats, the enhanced biliary excretion of bromcresol green was first observed at 12 h, it reached a peak at 24 h and returned to the control level at 72 h. Other groups of rats received 75 mg/kg phenobarbital as daily i.p. dose over 5 days. In these groups, the increase in biliary flow did not exceed that measured in the rats given the single dose, however, the biliary excretion of bromcresol green reached its peak after a 4-day phenobarbital treatment. After the 5th day of treatment the biliary flow and the biliary excretion of bromcresol green remained significantly stimulated for 4 days and the changes in these parameters regressed on the fifth day following the last injection of phenobarbital. The changes in liver weight appeared not to run closely parallel either with the increase in biliary flow or with the enhancement of biliary excretion of bromcresol green. It is suggested that the changes in biliary flow and in the biliary excretion of bromcresol green take place by different mechanisms after phenobarbital administration.

Animals↗
PubMed1979

Effect of sodium taurocholate on the hepatic transport of bromsulphthalein in rats.

In anaesthetized, bile duct-cannulated rats the hepatic transport of bromsulphthalein (BSP) showed a dose-dependent increase in response to simultaneous administration of taurocholate (TC). The excretion rates of both free (BSP) and conjugated bromsulphthalein (BSP-GSH) were significantly elevated by TC. The simultaneously given TC decreased the hepatic uptake of BSP and BSP-GSH, but did not influence the conjugation of BSP with glutathione (GSH) or the biliary excretion rate of exogenous BSP-GSH. When the liver was depleted of GSH by pretreatment with diethyl-maleate (DEM), TC increased the excretion of free BSP. In DEM-treated rats free BSP markedly depressed the biliary excretion of exogenous BSP-GSH. When TC was given simultaneously with BSP, the inhibitory effect of BSP on the excretion of exogenous BSP-GSH was significantly reduced. TC also diminished the depressing effect of BSP on state III respiration of liver mitochondria in vitro. It is concluded that this effect of TC may play a role also in the increased biliary excretion of intraphepatic conjugated BSP.

Animals↗
PubMed1979

Effect of sodium taurocholate on hepatic uptake and biliary excretion of organic anions in rats.

Hepatic uptake and biliary excretion of some exogenous organic anions administered simultaneously with sodium taurocholate (TC) have been investigated in anaesthetized (1.2 g/kg urethane i.p.) rats. TC (100 or 200 mumol/kg i.v.) significantly increased the biliary excretion of indocyanine green (ICG), bromcresol green (BCG), rose bengal (RB) and bromsulphthalein (BSP). The biliary excretion rates of eosine (EO) and bromsulphthalein-glutathione conjugate (BSP-GSH) were not affected by TC. However, simultaneously given TC significantly reduced the biliary excretion of amaranth (AM). The effect of TC on the biliary excretion rates of organic anions seems to depend on the properties of the anions investigated. ICG, BCG, RB and BSP depress bile production, inhibit mitochondrial respiration and are excreted at low rates. Biliary excretion of these anions was enhanced by TC. EO, BSP-GSH and AM had no depressing effect on the function of liver cells and showed higher excretory rates than the above-mentioned substances. The changes in biliary flow measured during excretion of drugs did not parallel the changes in biliary excretion rate. The hepatic uptake of all organic anions studied was depressed by TC. This finding indicates that no correlation exists between the effects of TC on hepatic uptake and biliary excretion of organic anions.

Animals↗
PubMed1979

Effect of 3-methylcholanthrene on the biliary excretion of bromsulphthalein and eosine in newborn rats.

The biliary excretion rates of bromsulphthalein (BSP), bromsulphthalein-glutathione conjugate (BSP-GSH) and eosine have been studied in 3-methylcholanthrene (3-MC)-pretreated (100 mg/kg i.p.) and control rats aged 10 days. Liver weight was invariably increased after 3-MC treatment, associated with enhanced biliary excretion of total BSP. The increase in the biliary excretion of total BSP was due solely to the increased excretion of BSP-GSH. Following 3-MC pretreatment, BSP-GSH and eosine appeared in the bile in the same amount as in the control rats after i.v. administration of BSP-GSH and eosine. Pretreatment with 3-MC increased the ratio of BSP-GSH to BSP in the liver and bile. Our results suggest that the increased biliary excretion of total BSP following 3-MC treatment was due to an enhanced conjugation of BSP with GSH.

Animals↗
PubMed1979

Correlation between hepatic transport of cholephilic organic anions and their effect on hepatic mitochondrial respiration.

The maximum biliary excretion rate (Tm) of some nonmetabolized organic anions was investigated in anaesthetized male rats and was found to increase in the following order: indocyanine green (ICG), rose bengal (RB), bromsulphthalein (BSP; its conjugation with glutathione was prevented by diethyl maleate), bromcresol green (BCG), eosine (E), BSP-glutathione conjugate (BSP-GSH), iodoxamic acid (IA) and amaranth (A). The accumulation of ICG, RB, BSP and BCG in liver was relatively high, whereas E, BSP-GSH,IA and A were taken up by the liver in a lower concentration. ICG, RB, BSP and BCG decreased the biliary flow, however, E, BSP-GSH, IA and A stimulated it. ICG, RB and BSP had a strong, BCG and E a moderate, inhibitory effect on hepatic mitochondrial respiration stimulated by ADP, DNP and glutamate-malate, whereas BSP-GSH, IA and A had no effect on this process. Our results suggest that the depressing effect of cholephilic organic anions on bile production and their low biliary excretion rates are connected with their inhibitory effects on mitochondrial respiration.

Amaranth Dye↗
PubMed1979

Hepatic microsomal induction and hepatic transport.

Hepatic microsomal induction (hexobarbital sleeping time, cytochrome P-450 and microsomal protein concentration, liver weight) and hepatic transport (hepatic uptake, biotransformation, biliary excretion) have been studied in rats. Phenobarbital pretreatment (75 mg/kg i.p. daily for 5 days) produced microsomal induction in the liver and enhanced biliary excretion of bromcresol green, eosine, bromsulphthaleine glutathione conjugate (BSP-GSH), amaranth and iodoxamic acid. However, biliary excretion of indocyanine green was unchanged after phenobarbital pretreatment. Biotransformation of bromsulphthalein (BSP) with glutathione was also increased by phenobarbital. The hepatic concentration of these organic anions was not influenced uniformly after phenobarbital pretreatment: the concentration of indocyanine green, bromcresol green, eosin and BSP-GSH in the liver was unchanged, that of amaranth and iodoxamic acid was enhanced following phenobarbital pretreatment. Investigation of the effect of pretreatment with other barbiturates showed that barbital, butobarbital, pentobarbital and amobarbital produced microsomal induction. Only baribtal and butobarbital stimulated biliary excretion of organic anions, whereas pentobarbital and amobarbital proved to be ineffective in this parameter. The results seem to indicate that the enhanced biliary excretion of exogenous organic anions produced by barbiturates is independent of microsomal enzyme induction.

Amaranth Dye↗
PubMed1978

Bile flow and biliary excretion rate of some organic anions in phenobarbital-pretreated rats.

Bile flow and the biliary excretion of indocyanine green, bromcresol green, eosine, bromsulphthalein-glutathione conjugate (BSP-GSH), amaranth and iodoxamic acid were investigated in control and phenobarbital-pretreated rats (75 mg/kg i.p. daily for 5 days). The bile flow was increased by phenobarbital from an average of 50.6 to 77.7 microliter/kg/min. Depending on the dose, the biliary excretion rate of bromcresol green was increased by 48-496% and that of eosine by 30-149%. After phenobarbital pretreatment the excretion of BSP-GSH was also enhanced by 34-52%, that of amaranth by 37-53% and that of iodoxamic acid by 40-56%. However, the biliary excretion of indocyanine green remained unchanged. There was no parallelism between the increase in bile flow and biliary excretion of the drugs.

Amaranth Dye↗
PubMed1978

Hepatic transport of sulphobromphthalein and sulphobromphthalein-glutathione conjugate in control and phenobarbital-pretreated rats.

The biliary excretion of intravenously administered sulphobromphthalein (BSP) and sulphobromphthalein-glutathione conjugate (BSP-GSH) has been studied in control and phenobarbital-pretreated rats (75 mg/kg intraperitoneally daily for five days). Hepatic utake and biliary excretion of free BSP have been investigated in rats pretreated with diethyl maleate (DEM), which depletes the liver of glutathione (GSH) and therefore inhibits the conjugation of BSP with GSH. Phenobarbital pretreatment caused no significant change in the hepatic uptake of BSP or BSP-GSH. The conjugation of BSP and GSH in phenobarbital-preatreated rats was significantly faster than in the controls. The biliary excretion of free BSP was unchanged after phenobarbital induction, but significantly more BSP-GSH was excreted than in the controls. Thus, both the faster conjugation and the enhanced transport of BSP-GSH into the bile canaliculi were responsible for the increased biliary excretion of BSP in phenobarbital pretreated rats.

Animals↗
PubMedDate not supplied

Effect of arsenicals on biliary excretion of endogenous glutathione and xenobiotics with glutathione-dependent hepatobiliary transport.

Sodium arsenite (25-100 mumol/kg, i.v.) and arsenate (75-300 mumol/kg, i.v.) injected into anaesthetized rats increased the biliary excretion of endogenous non-protein thiols (NPSH) in a dose-dependent fashion up to 24- and 31-fold, respectively. Simultaneously with NPSH, glutathione (GS) excretion was increased to a similar extent suggesting that the increment in biliary thiol output originated from enhanced hepatobiliary transport of GS. After administration of labelled arsenicals, biliary excretion of 74As and NPSH followed similar time-courses. Biliary excretion of 74As was more efficient after arsenite than arsenate administration corresponding to the greater potency of arsenite compared to arsenate to increase biliary output of NPSH. Coadministered sulfobromophthalein (BSP) inhibited the biliary excretion of 74As and prevented the arsenical-induced increase in biliary NPSH. Thus, hepatobiliary transport of arsenic apparently proceeds coordinately with that of GS. However, excretion of each molecule of arsenic compound generates transport of several molecules of GS. Though mercuric, methylmercuric, cadmium and zinc ions are thought to be excreted into bile as complexes with GS, the marked arsenical-induced increase in GS excretion only doubled the biliary excretion of inorganic mercury and hardly influenced the transport of other metals into bile. This finding suggests that arsenicals markedly enhance biliary excretion of GS with a free thiol group but barely or not at all that of GS with a thiol group blocked by a firmly bound metal ion. Both arsenicals diminished the biliary excretion of BSP-glutathione conjugate after BSP administration presumably because they impaired conjugation of BSP with GSH due to decreased GS availability. It is assumed that arsenite, and arsenate after reduction to arsenite, forms an unstable complex with GS that is efficiently transported into bile resulting in increased biliary output of GS. It is demonstrated that arsenite-induced perturbation of hepatobiliary disposition of endogenous GS differentially affects biliary excretion of xenobiotics with GS-dependent hepatobiliary transport.

Animals↗
PubMedDate not supplied

Availability of glycine and coenzyme A limits glycine conjugation in vivo.

Using benzoic acid as substrate, this study tested the hypothesis that capacity limitation of glycine conjugation in vivo is due to substrate-induced depletion of hepatic cosubstrates (i.e., ATP, coenzyme A, and glycine) utilized in the conjugation reaction. Benzolyglycine formation was investigated by following the disappearance of benzoic acid from blood and appearance of benzoylglycine in blood and urine after administration of sodium benzoate (0.2-2 mmol/kg, iv) to anesthetized rats whose urine formation was stimulated by mannitol administration. Capacity limitation of glycine conjugation is indicated by (a) the gradual dose-dependent reduction of benzoate blood clearance from 39 ml/min/kg at 0.2 mmol/kg benzoate to 3.7 ml/min/kg at 2 mmol/kg, and (b) the tendency to attain maximal blood levels and urinary excretion rates of benzoylglycine after administration of 0.5-1 mmol/kg benzoate. The maximal urinary excretion rate of benzoylglycine after benzoylglycine administration exceeded the maximal excretion rate of endogenously formed benzoylglycine (approximately 5 mumol/kg/min) 5-fold. This suggests that the urinary excretion rate of endogenously formed benzoylglycine reflects the rate of its formation. Benzoate depleted hepatic glycine (to 40%) and coenzyme A (to 14%) in a dose-dependent fashion; however, it did not change ATP levels in liver. The pattern of this dose-dependent cosubstrate depletion suggests that benzoate primarily causes consumption of hepatic glycine which, at high substrate dosage, leads to marked depletion of coenzyme A in the liver. Thus, these observations indicate that capacity-limited glycine conjugation may be due to limited availability of glycine and coenzyme A for the conjugation process.

Adenosine Diphosphate↗
PubMedDate not supplied

Homeostasis of sulfate and 3'-phosphoadenosine 5'-phosphosulfate in rats with deficient dietary intake of sulfur.

This study was designed to determine the role of dietary organic and inorganic sulfur on 3'-phosphoadenosine 5'-phosphosulfate (PAPS) homeostasis. Organic sulfur was altered by adding various amounts of methionine (0.15, 0.3, 0.6, or 1.2%) to a sulfhydryl-deficient diet. Inorganic sulfur was altered by providing rats with no sulfate or sulfate in their diets (0.12%) and distilled or tap water. Rats received these diets for 5 days. The two lowest methionine-containing diets produced a 60% reduction in liver glutathione concentrations, and the addition of sulfate to the diets did not restore hepatic glutathione levels. Urinary sulfate excretion was reduced by 95% in rats fed the three low-methionine diets. Addition of sulfate to these diets increased the urinary excretion of sulfate, but did not return sulfate levels to control values. The three low-methionine-containing diets decreased serum and liver sulfate concentrations about 50% and addition of sulfate to these diets largely restored them to control levels. Hepatic PAPS concentration was decreased (10%) only in the group receiving the lowest methionine content in their diet, and addition of sulfate had no effect on hepatic PAPS. In summary, dietary alterations of sulfur lowered the glutathione concentration in the liver as well as decreased sulfate levels in serum, liver, and urine, but had minimal effect on hepatic PAPS concentrations. Therefore, it appears that hepatic steady-state PAPS levels are not highly dependent on the sulfur content of the diet.

Amino Acids↗
PubMedDate not supplied

Effect of microsomal enzyme inducers on biliary and urinary excretion of acetaminophen metabolites in rats. Decreased hepatobiliary and increased hepatovascular transport of acetaminophen-glucuronide after microsomal enzyme induction.

Treatment of rats with phenobarbital (PB), 3-methylcholanthrene, and pregnenolone-16 alpha-carbonitrile increased the total (biliary plus urinary) excretion of thioether and glucuronic acid conjugates of acetaminophen (AA) without influencing AA-sulfate excretion, suggesting that these microsomal enzyme inducers enhance both cytochrome P-450-mediated toxication and UDP-glucuronosyltransferase-mediated detoxication of AA. However, induction with transstilbene oxide (TSO) did not increase the total excretion of AA-thioethers or AA-glucuronide and decreased AA-sulfate excretion. In addition, all inducers increased the ratio of AA metabolites excreted into urine over that excreted into bile. The extent of this shift from biliary to urinary excretion was dependent on both the AA metabolite and the inducer. The largest shift in the excretory route was seen with AA-glucuronide and induction with PB and TSO as inducers. Specifically, PB and TSO treatments decreased biliary excretion of AA-glucuronide by 70 and 89%, respectively, and increased its blood concentration up to 6- and 11-fold and urinary excretion 3- and 3.6-fold, respectively. Galactosamine depletes UDP-glucuronic acid from the liver only, thereby inhibiting hepatic but not extrahepatic glucuronidation. Galactosamine treatment prevented the PB-induced increase in AA-glucuronide in blood and urine. This suggests that the PB-induced increases in AA-glucuronide in blood and urine originated from the liver. Thus, microsomal enzyme inducers not only influence xenobiotic biotransformation, but may also after the contribution of the excretory routes (i.e. bile and urine) in the elimination of xenobiotic metabolites by changing the direction of hepatic transport.

Acetaminophen↗