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Biomedical subjects

M Vore

Publications and source records attributed to M Vore.

At least 55 records · Page 3Linked to original sources
PubMed1991

Hepatic clearance and biliary secretory rate maximum of taurocholate in the recirculating and single pass isolated perfused rat liver. Effects of the cholestatic agent, estradiol-17 beta-(beta-D-glucuronide).

The ability of the cholestatic steroid glucuronide, estradiol-17 beta-(beta-D-glucuronide) (E(2)17G), to inhibit the hepatic clearance (ClH) and biliary secretory rate maximum (SRm) of taurocholate was investigated in the recirculating and single pass isolated perfused male rat liver. In the recirculating perfused liver, E(2)17G (0, 2, 4, or 6 mumol) was added as a bolus dose to the reservoir at zero time while taurocholate was infused into the portal vein in increasing amounts (15, 30, 45, or 60 mumol/mL; 1 mL/hr for 15 min each). E(2)17G (4 mumol) caused a significant (P less than 0.05) inhibition of bile flow and bile acid secretion at 10-15 min during infusion of 15 mumol/hr taurocholate but did not inhibit the SRm which occurred at 42 min, indicating that E(2)17G had not caused an irreversible inhibition of taurocholate transport. E(2)17G (6 mumol) caused a profound and irreversible inhibition of bile flow attributable to retention of E(2)17G in the liver. The noncholestatic estradiol-3-(beta-D-glucuronide) (E(2)3G; 6 mumol) had no significant effect on bile flow or the SRm. In the single pass perfused liver (10 mL/min flow rate), E(2)17G (0, 1, 2, 5, or 10 nmol/mL) or E(2)3G (2 nmol/mL) was added to the perfusate resulting in a stable infusion to the liver. [3H]Taurocholate was infused into the portal vein in increasing amounts to give inflow concentrations (Cin) of 25, 50, 75 or 100 nmol/mL. In the absence of E(2)17G, taurocholate ClH decreased from 0.92 to 0.70 mL/min/g liver with increasing taurocholate concentrations. Neither E(2)17G nor E(2)3G altered the ClH of 25 nmol/mL taurocholate. E(2)17G (10 nmol/mL) inhibited bile flow and bile acid secretion first at 20-25 min, followed by inhibition of ClH of 75 and 100 nmol/mL taurocholate (35-60 min). In contrast, E(2)3G stimulated bile acid secretion and increased the SRm by 80%. Thus, at doses that did not block its own elimination, E(2)17G did not cause an irreversible inhibition of taurocholate transport into bile. E(2)17G did not directly inhibit the uptake of taurocholate into the liver but first inhibited the biliary excretion of taurocholate, resulting in its intrahepatic accumulation and decreased clearance from the perfusate.

Animals↗
PubMed1990

Characterization of [3H]estradiol-17 beta-(beta-D-glucuronide) binding sites in basolateral and canalicular liver plasma membranes.

The specific binding of [3H]estradiol-17 beta-(beta-D-glucuronide) ([3H]E217G) was examined in isolated basolateral (bLPM) and canalicular (cLPM) liver plasma membranes. Two distinct binding sites were identified in each membrane fraction by competition and saturation experiments. Binding parameters obtained from competition studies were: Kd1 = 26 nM, Bmax1 = 0.26 pmol/mg protein; Kd2 = 2.6 microM, Bmax2 = 27 pmol/mg protein for bLPM; and Kd1 = 81 nM, Bmax1 = 0.61 pmol/mg protein; Kd2 = 6.7 microM, Bmax2 = 79 pmol/mg protein for cLPM. Binding parameters obtained from saturation experiments were not significantly different. There was no Na+ requirement for binding. Kinetic dissociation experiments showed that binding was reversible and revealed two components. The dissociation rate constants did not vary with the method of dilution of radioligand, i.e. by "infinite" volume, or excess unlabeled ligand, thus ruling out the possibility of cooperativity. The ability of a series of compounds to inhibit the binding of [3H]E217G was also examined. In bLPM, taurocholate (TC), estrone sulfate (E1SO4) and bromosulfophthalein (BSP) were able to compete with both binding sites, whereas estriol-17 beta-(beta-D-glucuronide) (E317G), estriol-16 alpha-(beta-D-glucuronide) (E316G), testosterone glucuronide (TG), estradiol-3-(beta-D-glucuronide) (E23G), estriol-3-(beta-D-glucuronide) (E(3)3G), cholate and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) were able to inhibit binding to only the low-affinity site. In cLPM, only the cholestatic steroid D-ring glucuronides (E(3)17G, E(3)16G and TG) and TC were able to compete with both sites, whereas the non-cholestatic steroid A-ring glucuronides (E(2)3G and E(3)3G), BSP and DIDS competed for only the low-affinity site. Based on the observed substrate specificities, the low-affinity sites in bLPM and cLPM are postulated to represent multispecific organic anion carriers. The high-affinity site in cLPM may play a role in mediating steroid D-ring glucuronide-induced cholestasis.

Animals↗
PubMed1990

Mirex exposure inhibits the uptake of estradiol-17 beta(beta-D-glucuronide), taurocholate, and L-alanine into isolated rat hepatocytes.

The insecticides mirex and chlordecone have previously been found to suppress the biliary excretion of a wide variety of compounds. In the present studies, the effects of mirex, chlordecone, and phenobarbital on the uptake of two endogenous organic anions, estradiol-17 beta(beta-D-glucuronide) (E217G), an estrogen metabolite, taurocholate (TC), a common bile acid, and an essential amino acid, L-alanine (L-Ala) (0.5 mM), into isolated rat hepatocytes was investigated. Female Sprague-Dawley rats were orally dosed with mirex (12.5, 25, and 50 mg/kg) or chlordecone (6.25, 12.5, and 18.75 mg/kg) dissolved in corn oil for 3 days and isolated rat hepatocytes were prepared 2 days later. Rats were also dosed orally with phenobarbital (50 mg/kg on the first day and 80 mg/kg for the next 4 days) dissolved in distilled deionized water, and isolated hepatocytes were prepared on the sixth day. Mirex significantly reduced the uptake of both organic anions (0.5, 10, and 50 microM E2 17G; 10 microM TC) into hepatocytes by 40-70%, whereas chlordecone had no effect on their uptake. Mirex at 50 mg/kg significantly reduced the Vmax for the low- and high-affinity E217G uptake sites by 70% and decreased the Km for the low affinity uptake site by 60%. Mirex also significantly decreased the Vmax for TC uptake from 1.11 to 0.82 nmol/min/mg protein but had no effect on its Km (23.2 vs 22.9 microM). Mirex at 50 mg/kg was also found to reduce the uptake of 0.5 mM L-Ala by nearly 40%. Phenobarbital had no effect on the uptake of E217G (0.5 microM), TC (10 microM), or L-Ala (0.5 mM). Mirex treatment had no effect on hepatic plasma membrane Na+,K(+)- or Mg2(+)-ATPase activity. Neither mirex nor chlordecone at 50-100 microM had any effect on the uptake of 10 microM TC when added directly to hepatocytes from naive rats. These results indicate that mirex decreases the transport of organic anions and L-Ala across the basolateral domain of the hepatocyte in addition to its inhibitory effects on biliary excretion.

Adenosine Triphosphatases↗
PubMed1989

Monokine depression of bile flow in the isolated perfused rat liver.

Multiple system organ failure (MSOF) is a progressive dysfunction of vital organs that may develop in clinical settings such as sepsis or multiple trauma. One component of this syndrome is cholestasis and impaired liver function. The mechanism(s) for this liver failure (and the failure of other organs) remains obscure. Macrophages and Kupffer cells have been shown to secrete cytokines such as interleukin-1 and tumor necrosis factor. These cytokines mediate many aspects of the acute phase response, and they also can produce cellular injury. The purpose of this study was to evaluate the effects of a semipurified murine monokine preparation having interleukin-1 activity on bile flow in the rat isolated perfused liver (IPL). The monokine preparation produced a significant reduction of bile flow in the IPL system. The effect could not be explained by a venoocclusive phenomenon or residual endotoxin in the monokine preparation. We conclude that a semipurified monokine preparation having interleukin-1 but not tumor necrosis activity produced a significant depression of bile flow in the IPL, and we suggest that macrophage secretory product(s) may be responsible for the cholestasis in MSOF.

Animals↗
PubMed1989

Structure-activity relationship of the cholestatic activity of dihydrotestosterone glucuronide, allo bile acids and lithocholate.

Dihydrotestosterone glucuronide (DHTG), a series of 5 alpha-bile acids, or allo-bile acids (3 alpha-hydroxy-5 alpha-cholanic acid, 3-keto-5 alpha-cholanic acid and 3 beta-hydroxy-5 alpha-cholanic acid) and their normal bile acid analogues (3 alpha-hydroxy-5 beta-cholanic acid or lithocholate, 3-keto-5 beta-cholanic acid and 3 beta-hydroxy-5 beta-cholanic acid) were administered intravenously to female rats in order to determine their effects on bile flow. All agents caused a rapid and profound inhibition of bile flow which was dose-dependent. The logarithm of the dose vs the cholestatic response curve for DHTG, the allo-bile acids and lithocholate were all parallel. DHTG was the most potent congener and was two times more potent than 3-keto-5 alpha-cholanic acid and 5 times more potent than lithocholate. These data indicate that the glucuronic acid moiety and the trans configuration of the A and B rings of the steroid nucleus confer the greatest cholestatic potency.

Animals↗
PubMed1989

Predictors of response to high dose antipsychotics in chronic schizophrenics.

Significant numbers of chronic schizophrenic patients do not experience sufficient symptom relief from usual doses of antipsychotic medication. Clinicians must decide if high doses of antipsychotics should be tried. In this study baseline symptoms, drug levels, and the symptomatic effects of an acute stimulant challenge were examined before 14 subjects received a 50% increase in their antipsychotic dosing. The group as a whole did not improve. Several individuals with lower drug levels, high baseline hallucinations, and stimulant-induced improvement in hallucinations improved mildly after 3 weeks on the higher antipsychotic dose.

Adult↗
PubMed1988

Coregulation of C3-hydroxyl versus C17-hydroxyl glucuronidation of beta-estradiol in pregnancy and after treatment with phenobarbital or ethinyl-estradiol.

The glucuronidation of [3H]estradiol-17 beta at the C3 vs. the C17 hydroxyl groups was determined in female Sprague-Dawley rat liver microsomes. A high-performance liquid chromatography method was developed to resolve the glucuronide conjugates which were then quantitated by liquid scintillation counting. The rates of formation of 17 beta-estradiol 3-(beta-D-glucuronide) (E(2)3G) and 17 beta-estradiol 17-(beta-D-glucuronide) (E(2)17G) were 0.49 +/- 0.03 and 0.40 +/- 0.02 nmol/min/mg of protein, respectively. The apparent Km and Vmax of estradiol glucuronidation were determined in control, pregnant (day 19 of gestation), phenobarbital-treated (80 mg/kg/day i.p. for 5 days) and ethinylestradiol-treated (5 mg/kg/day i.p. for 5 days) female rats. The least-squares estimates of Km and Vmax values as well as the confidence contours of the joint sums of squares for the parameter spaces were calculated. The Vmax (nanomoles per minute per milligram of protein) for E(2)3G was significantly decreased from 0.94 to 0.57 in pregnancy and to 0.47 as a result of ethinylestradiol treatment. The Vmax values for E(2)17G were significantly different in control (0.43), pregnant (0.31) and ethinylestradiol-treated (0.27) rats. Phenobarbital treatment slightly increased the Vmax to 0.51 for E(2)17G whereas the Vmax for E(2)3G was unchanged (0.90) compared to controls. The Km (micromolar) for E(2)3G was 144 in the controls, 112 in pregnancy and 86 and 92 as a result of treatment with ethinylestradiol and phenobarbital, respectively. The Km for E(2)17G was 60 in the controls, 40 in pregnancy, 43 and 68 as a result of ethinylestradiol and phenobarbital treatment, respectively. None of the changes in Km were statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗
PubMed1987

High and low affinity binding of [3H]cholate to rat liver plasma membranes.

The transport of bile acids across sinusoidal and canalicular membranes of hepatocytes is characterized as carrier mediated. Such a carrier should specifically bind bile acids at physiological concentrations. We examined the binding of [3H]cholate to rat liver plasma membranes using a microcentrifugation technique and detected high (KD = 1.23 +/- 0.44 microM, Bmax = 21.8 +/- 3.3 pmol/mg protein) and low (KD = 1.97 +/- 1.33 mM, Bmax = 41.5 +/- 25.3 nmol/mg protein) affinity binding sites. Maximal binding was achieved within 15-45 sec and was stable for 2 min at 37 degrees. Binding to the high affinity site was reversible, was not Na+ dependent or attributable to vesicular uptake, and exhibited a broad pH optimum. Binding to this site was negligible or not detected in liver mitochondrial and microsomal fractions, was saturable, and was inhibited by other bile acids. The IC50 values for bile acids as inhibitors of [3H]cholate binding at the high affinity site were: taurocholate, 1.9 nM; glycodeoxycholate, 3.1 nM; chenodeoxycholate, 5.6 nM; taurochenodeoxycholate, 7.3 nM; glycochenodeoxycholate, 11 nM; lithocholate, 13 nM; taurodeoxycholate, 20 nM; glycocholate, 3.6 microM; and deoxycholate, 5.6 microM. [3H]Cholate specific binding was inhibited by 10(-5) M bromosulfophthalein, bilirubin and indocyanin green. These data support the hypothesis that the high affinity binding site represents a carrier which is shared by bile acids and nonbile acid organic anions.

Animals↗
PubMed1987

Binding of 3H-estradiol-17 beta-(beta-D-glucuronide), a cholestatic organic anion, to rat liver plasma membranes. Evidence consonant with identification of organic anion carriers.

The binding of 3H-estradiol-17 beta(beta-D-glucuronide) (3H-E2 17G), a cholestatic organic anion, was examined in rat liver plasma membranes, and two saturable, specific binding sites were identified. The binding parameters are Kd1 = 3.9 X 10(-7) M, Bmax1 = 69 pmol/mg of protein; Kd2 = 4.90 X 10(-6) M, Bmax2 = 495 pmol/mg of protein according to Scatchard analysis of equilibrium experiments. Kinetic dissociation experiments showed that 3H-E2 17G binding was reversible and revealed two components. The dissociation rate constants did not vary with the method of dilution of radioligand, i.e., by "infinite" volume, or excess unlabeled ligand, ruling out the possibility of cooperativity. The rate of association of 3H-E2 17G binding was very rapid, so that maximal binding was reached within 15 sec at 4 degrees. Na+ was not required for binding and binding was not decreased in the presence of high osmolarity buffer (125 mM sucrose), indicating that transport into vesicles was not involved. The ability of a series of compounds to inhibit the binding of 3H-E2 17G was also examined. Taurocholate, cholate, taurodehydrocholate, and testosterone glucuronide were identified as ligands selective for the high affinity site (site 1). The A- and D-ring glucuronide conjugates of estradiol and estriol, bromosulfophthalein, dibromosulfophthalein, and the glucuronide conjugates of phenolphthalein, 4-methylumbelliferone, and menthol inhibited binding of 3H-E2 17G to both sites. Morphine glucuronide, estradiol, and glucuronic acid did not inhibit binding to either site. The substrate specificities of binding to the low affinity site (site 2) are consistent with data characterizing the transport of these substrates in hepatocytes and supports the postulate that site 2 represents a non-bile acid organic anion carrier. Site 1 is postulated to represent a carrier shared by the bile acids and non-bile acid organic anions.

Animals↗
PubMed1987

Multiple carriers for uptake of [3H]estradiol-17 beta(beta-D-glucuronide) in isolated rat hepatocytes.

The transport of the cholestatic steroid glucuronide, 3H-estradiol-17 beta-(beta-D-glucuronide) (E2 17G), was examined in isolated female rat hepatocytes over a broad substrate concentration range (0.1-100 microM). Two different carrier systems were identified with the following kinetic parameters: Km1 = 4.54 microM; Vmax1 = 0.149 nmol/min/mg protein; Km2 = 149 microM; Vmax2 = 0.641 nmol/min/mg protein. Taurocholate and testosterone glucuronide selectively and competitively inhibited [3H]-E2 17G uptake at the high affinity site. Ki values calculated for taurocholate (43 microM) and testosterone glucuronide (28 microM) indicated that these two inhibitors were relatively weak competitors for this E2 17G transport site. Conversely, E2 17G inhibited [3H]taurocholate uptake into isolated hepatocytes (Ki = 43 microM). Bromosulfophthalein (10 microM) inhibited uptake of 0.5-50 microM [3H]-E2 17G by 55-85%, whereas morphine glucuronide (100 microM) had no significant effect on uptake of [3H]-E2 17G at these concentrations. The effects of taurocholate, testosterone glucuronide, bromosulfophthalein, and morphine glucuronide on [3H]-E2 17G uptake into isolated rat hepatocytes correlated with the ability of these agents to inhibit binding of [3H]-E2 17G to specific sites in rat liver plasma membranes. These data support the postulate that the two [3H]-E2 17G binding sites identified in female rat liver plasma membranes represent two distinct organic anion carriers and indicate that the high affinity site for [3H]-E2 17G represents a carrier that is shared by organic anions and bile acids.

Animals↗
PubMed1986

Characterization of covalent binding of N'-nitrosonornicotine in rat liver microsomes.

The metabolism of the carcinogenic nitrosamine, N'-nitrosonornicotine (NNN), to reactive intermediates which bind covalently was assessed using male Sprague-Dawley rat liver microsomes. The NADPH-dependent covalent binding of [14C]NNN was linear with time up to 90 min and protein concentration up to 3.0 mg/ml. The apparent Km and Vmax of the binding were determined from the initial velocities and found to be 0.91 mM and 4.7 pmol/min/mg protein, respectively. Although NNN is not a hepatocarcinogen, this amount of NADPH-dependent covalent binding is 7-fold greater than that reported for dimethylnitrosamine, a potent hepatocarcinogen. Extensive covalent binding of [14C]NNN to liver and muscle microsomal protein was also present in the absence of an NADPH-generating system and in the presence of 50% methanol, indicating a non-enzymatically mediated reaction. Addition of the nucleophiles glutathione, cysteine and N-acetylcysteine significantly decreased (p less than 0.01) the non-NADPH-dependent binding, but did not affect NADPH-dependent binding. In vitro addition of the cytochrome P-450 inhibitors metyrapone, piperonyl butoxide and SKF-525A significantly decreased (p less than 0.05) NADPH-dependent binding of [14C]NNN by 27-40%. NADH did not replace NADPH in supporting covalent binding. Replacement of an air atmosphere with nitrogen or CO:O2 (8:2) significantly decreased (p less than 0.05) NADPH-dependent binding of [14C]NNN by 40 and 27%, respectively. Aroclor 1254 pre-treatment of the rats did not enhance the NADPH-dependent binding of [14C]NNN. These data indicate that cytochrome P-450 is at least in part responsible for the metabolic activation of the carcinogen NNN but also suggest additional mechanisms of activation.

Amino Acids↗
PubMed1986

Taurocholate and steroid glucuronides: mutual protection against cholestasis in the isolated perfused rat liver.

Estradiol-17 beta-(beta-D-glucuronide) (E217G) was shown to be cholestatic in the isolated perfused female rat liver. Doses of 0.85, 1.3, 1.7 and 2.1 mumol decreased bile flow maximally at 15 to 30 min by 29, 37, 68 and 76% respectively. Approximately 95% of a dose of [3H]E217G was cleared from the perfusate in 30 min and was secreted in bile, with 93, 85, 71 and 55% of the dose appearing in bile within 120 min after doses of 0.85, 1.3, 1.7 and 2.1 mumol, respectively. Neither vehicle nor 1.7 mumol of estradiol-3-(beta-D-glucuronide) (E23G) significantly altered bile flow. Infusion of taurocholate at 40 and 60 mumol/hr, respectively, partially and completely protected against the cholestasis induced by 1.7 mumol of E217G. The log dose-response curve for E217G-induced cholestasis was much steeper and was shifted to the right in the presence of a 60 mumol/hr infusion of taurocholate. Infusion of taurocholate at 80 mumol/hr in the absence of E217G or E23G decreased bile flow by 79%. However, addition of 1.7 mumol of either E217G or E23G offered marked protection against taurocholate-induced cholestasis and increased bile acid secretion. Higher doses (3.4 mumol) of E217G or E23G further increased bile flow and bile acid secretion. A model system is presented to explain the mutual protection against cholestasis.

Animals↗
PubMed1985

Cardiovascular and pharmacokinetic consequences of combined administration of verapamil and propranolol in dogs.

Verapamil and propranolol, alone and in combination, were given intravenously to anesthetized dogs to analyze the interaction between drug-induced cardiovascular effects and the resulting changes in pharmacokinetics. Dosing regimens were used that produced steady state plasma levels of both drugs, and the observed effects were clearly related to the plasma concentrations of the agents. When given alone, at stable "therapeutic" levels in plasma, verapamil or propranolol decreased spontaneous heart rate, increased atrioventricular conduction time, and had opposite effects on cardiac output. At the same doses, the combined infusion of the 2 drugs rapidly resulted in profound depression in cardiac function; in addition, plasma concentrations of both agents increased into ranges associated with cardiovascular toxicity. When verapamil doses were reduced, combined infusion with propranolol decreased atrioventricular conduction and cardiac output, but drug plasma concentrations (and associated effects) remained stable. When reduced doses of propranolol were added to infusion of verapamil, similar effects on cardiovascular function occurred, but plasma drug levels increased progressively throughout the remainder of the study period. In all combinations studied, beta blockade with propranolol decreased liver plasma flow and, therefore, the systemic clearance of verapamil. The in vitro effects of propranolol on verapamil metabolism were small, although significant, and not clinically relevant. These acute studies suggest that the hemodynamic effects resulting from verapamil and propranolol in combination may significantly diminish clearance of 1 or both drugs, thereby resulting in accumulation during continued administration, increased drug effects with increasing plasma concentrations, and potentially lethal drug toxicity.

Animals↗
PubMed1985

Effects of phenobarbital and SKF-525A on in vitro hepatic metabolism of verapamil and nifedipine.

Both verapamil and nifedipine are first-generation calcium-entry antagonist drugs which are eliminated by hepatic metabolism. To evaluate the effects of enzyme induction and suppression on the biotransformation of these compounds, liver homogenate fractions were prepared from male Fisher (F344) rats, which were either untreated, or injected intraperitoneally with phenobarbital or with SKF-525A prior to sacrifice. Known concentrations of verapamil or nifedipine were incubated with the 9,000 g supernatant, and the quantity of unchanged drug remaining after 10 min was measured. SKF-525A pretreatment significantly decreased the elimination (disappearance) rate of both calcium-entry antagonist compounds. Phenobarbital increased the rate of disappearance of verapamil, but had no effect on that of nifedipine. Difference spectra of hepatic microsomes to which verapamil had been added revealed a concentration-dependent, saturable interaction between drug and enzymes with spectral changes characteristic of "type I' substrates for cytochrome P-450 monooxygenase(s). The spectral characteristic of microsomes to which nifedipine was added could not be determined because of drug absorption at 350-500 nm. These data imply that verapamil metabolism is mediated by the cytochrome P-450 monooxygenase(s), and that nifedipine metabolism likely involves hepatic enzyme systems other than those known to be induced by phenobarbital.

Animals↗
PubMed1985

Effect of hypoxia and pregnancy on antipyrine metabolism in isolated perfused rat livers.

The effect of hypoxia on antipyrine metabolism was studied in isolated perfused livers from pregnant (19-21 days gestation) and nonpregnant female Wistar rats. Hypoxia was induced by altering the blood content and/or flow rate of the recirculating perfusion medium. Inflow and outflow pO2 values, in themselves, were not valid indicators of oxygen delivery and consumption when the liver was perfused with a blood containing medium. At a given oxygen delivery rate, oxygen consumption per gram of liver was the same in nonpregnant and pregnant rat livers. The absolute clearance of antipyrine (milliliters per hour) was significantly greater in livers from pregnant compared to nonpregnant rats, whereas antipyrine clearance, corrected for liver weight (milliliters per hour gram of liver), was significantly lower in pregnant rat livers. Antipyrine clearance (milliliters per hour) was linearly related to oxygen consumption (milliliters per minute or micromoles per minute per gram of liver) in both the nonpregnant and pregnant rat livers. As oxygen consumption decreased, livers from pregnant rats maintained a greater ability to clear antipyrine than livers from nonpregnant rats. This study emphasizes the importance of maintaining adequate oxygen delivery to isolated perfused livers during drug metabolism studies to ensure constant oxygen consumption. Otherwise, alterations in the flow rate or hematocrit of the perfusion medium may directly alter the elimination rate of the substrate.

Animals↗
PubMed1984

Characterization of the interaction between estrogen metabolites and taurocholate for uptake into isolated hepatocytes. Lack of correlation between cholestasis and inhibition of taurocholate uptake.

The cholestasis induced by estrogen metabolites has been postulated to be due to an inhibition of bile acid transport. Therefore, the uptake of [3H]taurocholate (TC) into isolated hepatocytes was examined in the presence of known cholestatic steroid glucuronides. The cholestatic D-ring glucuronide conjugates of estradiol, estriol, ethynylestradiol and dihydrotestosterone did not inhibit the uptake of TC suggesting that these organic anions are transported by different carrier systems. Estrone sulfate inhibited TC uptake 65% but did not decrease bile flow following i.v. administration to the rat (22 mumol/kg), under conditions which the steroid glucuronide estradiol-17 beta-(beta-D-glucuronide) ( E217G ) decreased bile flow 100%. The hepatocytic uptake of [3H] E217G (100 microM) was inhibited by estriol-16 alpha-(beta-D-glucuronide) (200 microM, 40%) and estradiol-17 beta-3-(beta-D-glucuronide) (200 microM, 22%) as well as by the organic anions bromosulfophthalein (150 microM, 57%), dibromosulfophthalein (150 microM, 59%), indocyanine green (150 microM, 62%), rose bengal (150 microM, 56%) and bilirubin (50 microM, 40%). Thus, the bile acids and steroid glucuronides are transported into the hepatocyte by different carrier systems so that the cholestasis induced by the steroid D-ring glucuronides cannot be explained by an inhibition of bile acid uptake. Furthermore, the hepatocytic uptake of E217G occurs by a carrier system similar to that for the other steroid glucuronides and organic anions.

Animals↗