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PubMed1996

Pharmacokinetics of the new thyrotropin releasing hormone analogue montirelin hydrate. 2nd communication: distribution and transfer into the fetus and milk after a single intravenous administration and pharmacokinetics and enzyme induction after repeated intravenous administration to rats.

Pharmacokinetics of 14C-labeled montirelin hydrate (CAS 90243-66-6, NS-3) in rats was studied after single or repeated intravenous administration. 1. Radioactivity concentrations in tissues after single administration to male and female rats were highest in the kidney followed (in this order) by plasma, liver, blood, pancreas, uterus (female rats), lung and skin and low in various brain sites 5 min after administration. The concentrations in most tissues were practically parallel to those in plasma over the 24-h period after administration. After decreasing rapidly the concentrations rose slightly for 10 h and then decreased gradually. 2. Five min after single administration to male rats, the concentration of the main metabolite CNK-6004 (deamidated product) was lower in the plasma, but higher in the liver and kidney than the NS-3 concentration. From 0.5 to 2 h after administration, the concentration of CNK-6004 was higher than that of NS-3 in the plasma, liver and kidney, accounting for 33-64% of the radioactivity concentration. 3. After administration to rats on the 18th day of pregnancy, the radioactivity concentrations in the fetal whole body and fetal tissues peaked later than those in the maternal plasma, tissues and placenta. The maximum concentration in the fetal tissues was 2% or less of that in the maternal plasma. 4. After administration to lactating rats, the radioactivity concentration in milk reached the maximum 10 h after administration, and decreased gradually in parallel with the concentration in the plasma 24 to 168 h after administration. 5. During repeated once daily administration for 10 days, the radioactivity concentration in the plasma 24 h after each administration reached practically steady state level after the 7th administration and decreased with a half-life of 38.1 h after the last administration. 6. The radioactivity concentrations in most tissues after the last administration were not significantly different from those after a single administration. Decreased elimination of the radioactivity was observed in the white fat and skin, in which radioactivity levels were higher than those in the other tissues a long time after the last dose. 7. Excretion of the radioactivity in the urine and feces during repeated administration was constant after the 2nd administration. The excretion by 168 h after the last administration was 66.9 and 14.3% of the cumulative dose in the urine and feces, respectively (total: 81.2%). 8. The composition of metabolites in the plasma, liver, kidney and urine after the last administration did not differ markedly from that after a single administration. Once daily repeated administration for 7 days had no effect on the liver drug metabolizing enzyme activities.

Animals↗
PubMed1990

Pharmacokinetics of 4-acetylaminophenylacetic acid. 2nd communication: tissue accumulation and enzyme induction in rats after repeated administration, and placental and milk transfer after single dosing.

The absorption, distribution, metabolism and excretion of 14C-labeled 4-acetylaminophenylacetic acid (MS-932) were studied in male rats after administration of an oral dose of 10 mg/kg once a day for 21 days. Comparison with the single dosing showed no marked alterations in absorption, distribution, metabolism and excretion. There were no significant differences in the activities of hepatic aniline hydroxylase and aminopyrine N-demethylase between the MS-932 treated group (10 mg/kg for 8 days) and the 0.5% aqueous sodium carboxymethyl cellulose control group (p greater than 0.05). Placental transfer of radioactivity was studied after single oral administration of 10 mg/kg of 14C-MS-932 to pregnant rats on the 12-13th and 19-20th days of gestation. Radioactivity concentrations were highest in the maternal plasma and lowest in the amniotic fluid and fetus for both middle and late pregnancies. The concentrations in the amniotic fluid and fetus decreased more slowly than did the concentration in the maternal plasma. Excretion of radioactivity to milk was studied after single oral administration of 10 mg/kg of 14C-MS-932 to lactating rats on the 10th day after parturition. Radioactivity concentrations in the rat milk were maximal at 1 h after dosing and were lower than in the maternal plasma at all the sampling times.

Aminopyrine N-Demethylase↗
PubMed1979

An animal model of halothane hepatotoxicity: roles of enzyme induction and hypoxia.

Exposure of phenobarbital-pretreated male Sprague-Dawley rats to halothane, 1 per cent, for two hours under conditions of hypoxia (FIO2 0.14) resulted in extensive centrilobular necrosis within 24 hours. Accompanying the morphologic damage were an increase in serum glutamic pyruvic transminase (SGPT) and a decrease in hepatic microsomal cytochrmoe P-450. Glutathione levels in the liver were unchanged. Phenobarbital-pretreated rats anesthetized with halothane, 1 per cent, at FIO2 0.21 had only minor morphologic changes at 24 hours. Hepatic injury was not apparent in any non-phenobarbital-induced rat or in any induced animal exposed to ether at FIO2 0.10 or to halothane at FIO2 0.99. There was a 2.6-fold increase in the 24-hour urinary excretion of fluoride in those rats in which extensive centrilobular necrosis developed. The in-vivo covalent binding to lipids of 14C from 14C-halothane also was increased markedly when 14C-halothane was administered intraperitoneally to phenobarbital-induced rats maintained hypoxic (FIO2 0.14) for two hours. These results support the authors' hypothesis that halothane is metabolized to hepatotoxic intermediates by a reductive or non-oxygen-dependent cytochrome P-450-dependent pathway. This animal model of halothane-induced hepatotoxicity may be clinically relevant. A decrease in hepatic blood flow during halothane anesthesia may decrease the PO2 available to hepatocytes and thus direct the metabolism of halothane along its reductive, hepatotoxic pathway.

Alanine Transaminase↗
PubMed1990

Effect of enzyme induction on Sandimmun (cyclosporin A) biotransformation and hepatotoxicity in cultured rat hepatocytes and in vivo.

This study was designed to examine the relationship between the extent of Sandimmun (cyclosporin A, SIM) metabolism and SIM-induced hepatotoxicity both in vivo and in primary cultures of rat hepatocytes. Firstly, SIM (50 mg/kg p.o.) was administered daily to male Wistar rats for 10 days with or without co-administration of Aroclor 1254. SIM-induced hepatotoxicity appeared after 4 days of treatment and was enhanced after 10 administrations of SIM. Total plasma proteins were decreased and hyperbilirubinemia as well as increased levels of plasma bile salts were prominent. Aroclor 1254 stimulated total hepatic cytochrome P-450 3.7-fold, and markedly increased the rate of SIM metabolism and plasma elimination as determined by both HPLC and RIA techniques. However, this induction did not change the degree of SIM-induced hepatotoxicity. Secondly, short-term cultures of hepatocytes obtained from normal rats and from rats pretreated with either Aroclor 1254 or dexamethasone, a specific inducer of the cytochrome P-450 III gene family responsible for the formation of the primary SIM metabolites M1, M17 and M21, were incubated with various concentrations of SIM for up to 17 hr. At 1 microM SIM, both inducers greatly increased the rate of SIM metabolism in vitro, producing, however, different metabolite patterns. In the hepatocyte cultures, SIM inhibited the incorporation of amino acids into proteins. In addition, a small fraction of [3H]-labeled SIM was covalently bound to hepatocellular macromolecules. Although the fraction of covalently bound SIM was markedly increased in cells from dexamethasone-treated rats, the degree of inhibition of hepatocellular protein synthesis was not changed in cells from induced rats. In contrast to SIM-induced nephrotoxicity, these results suggest that increased rates of SIM biotransformation by inducers of drug metabolism are not associated with an attenuation of hepatotoxicity both in vivo and in vitro.

7-Alkoxycoumarin O-Dealkylase↗
PubMed2006

Sulforaphane-stimulated phase II enzyme induction inhibits cytokine production by airway epithelial cells stimulated with diesel extract.

Airborne particulate pollutants, such as diesel exhaust particles, are thought to exacerbate lung and cardiovascular diseases through induction of oxidative stress. Sulforaphane, derived from cruciferous vegetables, is the most potent known inducer of phase II enzymes involved in the detoxification of xenobiotics. We postulated that sulforaphane may be able to ameliorate the adverse effects of pollutants by upregulating expression of endogenous antioxidant enzymes. Stimulation of bronchial epithelial cells with the chemical constituents of diesel particles result in the production of proinflammatory cytokines. We first demonstrated a role for phase II enzymes in regulating diesel effects by transfecting the airway epithelial cell line (BEAS-2B) with the sentinel phase II enzyme NAD(P)H: quinine oxidoreductase 1 (NQO1). IL-8 production in response to diesel extract was significantly reduced in these compared with untransfected cells. We then examined whether sulforaphane would stimulate phase II induction and whether this would thereby ablate the effect of diesel extracts on cytokine production. We verified that sulforaphane significantly augmented expression of the phase II enzyme genes GSTM1 and NQO1 and confirmed that sulforaphane treatment increased glutathione S-transferase activity in epithelial cells without inducing cell death or apoptosis. Sulforaphane pretreatment inhibited IL-8 production by BEAS-2B cells upon stimulation with diesel extract. Similarly, whereas diesel extract stimulated production of IL-8, granulocyte-macrophage colony-stimulating factor, and IL-1beta from primary human bronchial epithelial cells, sulforaphane pretreatment inhibited diesel-induced production of all of these cytokines. Our studies show that sulforaphane can mitigate the effect of diesel in respiratory epithelial cells and demonstrate the chemopreventative potential of phase II enzyme enhancement.

Base Sequence↗
PubMed1995

Glutathione S-transferases from larval Manduca sexta midgut: sequence of two cDNAs and enzyme induction.

Two glutathione S-transferase (GST) clones from a larval midgut cDNA library of the tobacco hornworm, Manduca sexta were sequenced. The nucleotide sequence of the first clone, M. sexta GST1, encoded a protein of 217 amino acids with a predicted molecular weight of 24,644 and isoelectric point of 4.8. The M. sexta GST1 was 45.9-48.6% identical to GSTs from Musca domestica and several Drosophila species. The M. sexta GST2 cDNA encoded a protein of 203 amino acids with a predicted molecular weight of 23,596 and isoelectric point of 5.5. The M. sexta GST2 shared 44.8-50.0% sequence identity to a second cluster of insect GSTs from M. domestica, D. melanogaster and Anopheles gambiae. GST1 and GST2 were only 24.1% identical in amino acid sequence. The divergence of these two classes of insect GSTs occurred before the radiation of Diptera and Lepidoptera. Northern analysis of the expression of these GSTs showed increased GST1 mRNA levels in midguts of larvae fed diets containing 2-undecanone, or phenobarbital. Midgut and fat body cytosolic GST activities were induced when larvae were fed diets containing 2-tridecanone, 2-undecanone, or phenobarbital. Partial purification of midgut GSTs by size-exclusion and glutathione affinity chromatography resulted in a series of isoelectric focusing bands, with the major one corresponding to the predicted isoelectric point of the M. sexta GST1. In summary, two midgut GSTs have been identified on the basis of cDNA sequence and one of these, GST1, was inducible by dietary chemicals.

Amino Acid Sequence↗
PubMed1996

Interactive effects between 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,2',4,4',5,5'-hexachlorobiphenyl in female B6C3F1 mice: tissue distribution and tissue-specific enzyme induction.

The distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) was studied in female B6C3F1 mice. Single doses of TCDD alone (0, 0.1, 1, or 10 micrograms [3H]TCDD/kg), PCB 153 alone (0, 3.58, 35.8, or 358 mg [14C]PCB 153/kg), and all possible combinations of these doses were administered in corn oil, po. At 7 days after dosing, 11 different tissues were analyzed for radioactivity. When TCDD was administered alone, TCDD-derived radioactivity distributed to all tissues in a dose-dependent manner, increasing with dose in the liver, while decreasing (as a percentage of the administered dose) in all other tissues. When PCB 153 was administered alone, the PCB 153 concentration was dose-dependently (percentage of dose) decreased in liver, skin, lung, adrenals, kidney, and blood; no dosimetric effects were observed in the other organs. Coadministration of low doses of both TCDD and PCB 153 resulted in little or no effect on the distribution of either compound. Interactive effects occurred in the pharmacokinetic behavior of both compounds only at higher doses. For example, the amount of TCDD in the liver was increased by 358 mg PCB 153/kg. In most other organs administration of PCB 153 resulted in a dose-dependent decrease in the TCDD content. Coadministration of PCB 153 with 10 micrograms TCDD/kg increased PCB 153 in the liver, but not in other tissues. These results clearly demonstrate that interactive effects on pharmacokinetic behavior occur only at high doses.

Adipose Tissue↗
PubMed1990

The structure-dependent effects of heptachlorodibenzofuran isomers in male C57BL/6 mice: immunotoxicity and monooxygenase enzyme induction.

The dose-response effects of the 1,2,3,4,6,7,8-, 1,2,3,4,7,8,9-, 1,2,3,4,6,8,9-, and 1,2,3,4,6,7,9-heptachlorodibenzofurans (HpCDFs) on the splenic plaque-forming cell (PFC) response to sheep erythrocytes and on the induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin-O-deethylase (EROD) activities were determined in male C57BL/6 mice. The ED50 values for the decrease in the PFCs/spleen, the number of PFCs/10(6) viable cells, and the induction of AHH and EROD activities were 1,2,3,4,6,7,8-HpCDF, 0.011, 0.018, 0.11, and 0.315 mumol/kg, respectively; 1,2,3,4,7,8,9-HpCDF, 0.012, 0.054, 0.70, and 0.20 mumol/kg, respectively; 1,2,3,4,6,7,9-HpCDF, 1.2, 1.3, greater than 43, and greater than 43 mumol/kg, respectively; 1,2,3,4,6,8,9-HpCDF, 1.5, 3.4, 22, and 22 mumol/kg, respectively. It was apparent from these studies that the 2,3,7,8-substituted HpCDF isomers (1,2,3,4,6,7,8- and 1,2,3,4,7,8,9-) were significantly more potent than the compounds which contained only three lateral C1 groups. These results were obtained using a multiple dosing regimen in which 10 separate doses of the HpCDF isomers were administered to the mice by intraperitoneal injection over a period of 12 days. However, when the mice were treated with a single dose of an HpCDF congener, which was equivalent to the total dose used in the multiple dose study, the responses were comparable. A comparison of the relative immunotoxic potencies of the 2,3,7,8-substituted HpCDFs and 2,3,7,8-tetrachlorodibenzo-p-dioxin showed that the latter compound was approximately 10 times more active than the HpCDFs.

Animals↗
PubMed1996

Cytochrome P4501A2: enzyme induction and genetic control in determining 4-aminobiphenyl-hemoglobin adduct levels.

Cytochrome P4501A2 (CYP1A2) activity may be related to bladder cancer risk through metabolic activation of aromatic amines, such as 4-aminobiphenyl (ABP), to reactive intermediates that can form DNA and hemoglobin (Hb) adducts. In the context of a study on smoking and bladder cancer risk, 97 healthy male volunteers were investigated. CYP1A2-dependent N-oxidation activity was measured using a molar ratio of urinary caffeine metabolites [(paraxanthine + 1,7-dimethyluric acid)/caffeine] obtained between the fourth and fifth h after drinking a standardized cup of coffee. N-Oxidation activity was induced by blond tobacco smoke, meat consumption the dinner before the test, or more than four cups of coffee a day. The regular use of medication appeared associated with a decrease in N-oxidation levels. Age and alcohol consumption were not related with CYP1A2 activity. A polymorphic distribution of the CYP1A2 and N-acetyltransferase-2 (determined by the caffeine metabolite ratio 5-acetylamino-6-formylamino-3-methyluracil:1-methylxanthine) phenotypes was examined in relation to susceptibility to ABP-Hb adduct formation. Rapid oxidizers and subjects with the combined slow acetylator-rapid oxidizer phenotype showed the highest ABP-Hb adduct levels at a low smoking dose. Blond tobacco smokers exhibited higher adduct levels compared with black tobacco smokers, after adjustment for the quantity of cigarettes smoked. At the highest levels of smoking exposure, no major difference in ABP-Hb adduct levels was found among the different combinations of CYP1A2 and N-acetyltransferase-2 phenotypes. In a subset of only 45 available samples, no association was seen between the ABP-Hb adduct levels and the glutathione S-transferase M1 genotype.

Age Factors↗
PubMed1975

Analysis of enzyme induction in bacteria.

The theoretical relations between the induced initiation and accumulation of lac mRNA and its translation are derived, taking the kinetics of repressor-operator dissociation and enzyme maturation into account. These relations are used to evaluate observed data on lac induction and to estimate a number of parameters that characterize the transcription and translation of the beta-galactosidase gene in the bacterium Escherichia coli B/r growing at three different rates (0.7-2.1 doublings/h).

Enzyme Induction↗
PubMed1983

The effect of enzyme induction on the stereoselective metabolism of optically pure (-)1R,2R- and (+)1S,2S-dihydroxy-1,2-dihydrobenz-[a]anthracenes to vicinal 1,2-dihydrodiol 3,4-epoxides by rat liver microsomes.

The optically pure (-) and (+)trans-1,2-dihydroxy-1,2-dihydrobenz[a]anthracenes (BA trans-1,2-dihydrodiol) were obtained through the resolution of their diastereomeric di(-)menthoxyacetates by normal-phase h.p.l.c., followed with base-catalyzed hydrolysis. The (-)-BA trans-1,2-dihydrobiol has been determined to have 1R,2R absolute stereochemistry by exciton chirality method. Each of the enantiomeric and racemic BA trans-1,2-dihydrodiol was incubated with liver microsomes from untreated, phenobarbital (PB)-, and 3-methylcholanthrene (MC)-treated male Sprague-Dawley rats. The racemic and enantiomeric BA trans-1,2-dihydrodiols were each metabolized to two 1,2,3,4-tetrahydroxy-1,2,3,4-tetrahydrobenz[a]anthracenes (BA 1,2,3,4-tetrol) derived from the hydrolysis of BA trans-1,2-dihydrodiol anti-3,4-epoxide (the 3,4-epoxy oxygen is trans to the 1-hydroxyl group) and syn-3,4-epoxide (the 3,4-epoxy oxygen is cis to the 1-hydroxyl group), respectively. All the BA 1,2,3,4-tetrols were identified by comparing the reversed-phase h.p.l.c. retention times of tetrols and their vicinal acetonides with the hydrolysis products of the chemically synthesized BA trans-1,2-dihydrodiol anti-3,4-epoxide, BA trans-1,2-dihydrodiol syn-3,4-epoxide, BA trans-3,4-dihydrobiol anti-1,2-epoxide, and BA trans-3,4-dihydrodiol syn-1,2-epoxide, respectively, by their modes of forming vicinal acetonides, and by ultraviolet absorption and mass spectral analyses. From the metabolism of (-)-BA trans-1,2-dihydrodiol, a BA trans-1,2-dihydrodiol anti-3,4-epoxide was the major product formed by liver microsomes from MC-treated rats whereas a BA trans-1,2-dihydrodiol syn-3,4-epoxide was the major product formed by liver microsomes from either untreated or PB-treated rats. In contrast, BA trans-1,2-dihydrodiol syn-3,4-epoxide was the major product formed from the metabolism of (+)-BA trans-1,2-dihydrodiol by all three rat liver microsomal preparations. Liver microsomes from PB-treated rats were found to catalyze the metabolism of both the racemic and the enantiomeric BA trans-1,2-dihydrodiols at a rate higher than those by liver microsomes from untreated and MC-treated rats. All BA 1,2,3,4-tetrol metabolites were found to be optically active by circular dichroism spectral analysis. The results indicate that the 'bay-region' BA trans-1,2-dihydrodiol is metabolized by rat liver microsomes predominantly at the vicinal 3,4-double bond and that each enantiomeric BA trans-1,2-dihydrodiol is metabolized to a pair of diastereomeric BA trans-1,2-dihydrodiol 3,4-epoxides with varying degrees of stereoselectivity depending on the constitutive forms of cytochrome P-450 in the rat liver microsomal preparations.

Animals↗
PubMed1990

Dose dependent enzyme induction by oxcarbazepine?

Antipyrine half life and clearance was compared in four patients with classical idiopathic trigeminal neuralgia during carbamazepine (CBZ) or CBZ/phenytoin (PHT) and after substitution with oxcarbazepine (OXC) monotherapy. OXC is observed to be less of a hepatic enzyme inducer than CBZ or CBZ/PHT in combination, however induction by OXC may be dose related.

Aged↗
PubMed1983

Enzyme induction by estrogen.

The injection of estrogen into an immature or ovariectomized rat results in an increase in the specific activities of many uterine enzymes which can be detected, usually, within hours to days. The recent identification of the "estrogen-induced protein" as the brain type isozyme of creatine kinase (CKBB), provided an easily measurable enzyme marker, the mRNA of which doubles 1 h after estrogen injection. The increase in synthesis of CKBB from a high constitutive rate to a several-fold higher induced rate may be a more general response to hormonal stimulation in a mammalian system than the "all or none" induction exemplified by bacterial systems. This rapid estrogen-induced increase in the rate of CKBB synthesis is now reported in several rat reproductive organs; ovary, uterus, vagina and estrogen receptor-rich regions of the hypothalamus (anterior hypothalamus and median basal eminence) and preoptic areas, as well as in normal human breast tissue and in human breast tumors. The rapidity of CKBB induction makes it a favorable candidate marker for developing a cell-free induction system to study the interaction of the estrogen-receptor complex with specific loci in chromatin. For this purpose, molecular cloning of cDNA for CKBB is now under way.

Animals↗
PubMed1979

Manganese and zinc blockade of enzyme induction: studies with microsomal heme oxygenase.

Heme oxygenase (decyclizing) [heme,hydrogen-donor:oxygen oxidoreductase (alpha-methene-oxidizing, hydroxylating), EC 1.14.99.3] is greatly induced in the kidney by the administration of nickel or tin. Manganese, when administered simultaneously with nickel or tin in an equimolar amount, substantially inhibited the induction of heme oxygenase. The extent of inhibition was 80% and 98%, respectively. In rats pretreated up to 8 hr with manganese, the level of induction of heme oxygenase by nickel or tin was markedly reduced in a time-dependent fashion. Manganese treatment after the inducing metal was relatively ineffective in preventing the induction of heme oxygenase. Manganese in vitro did not inhibit heme oxygenase in the microsomes isolated from either control or tin-induced rats and in vivo did not increase the rate of catabolism of the induced enzyme. Magnesium was unable to block nickel or tin induction of heme oxygenase. Zinc in equimolar amounts could also substantially reduce the extent of induction of renal heme oxygenase when administered simultaneously with nickel or tin. In addition, simultaneous zinc administration blocked to a considerable extent the induction of hepatic heme oxygenase by nickel, cobalt, or cadmium. These findings indicate the existence of metal-metal interactions that can greatly influence the regulatory mechanism for the induced synthesis of heme oxygenase, the rate-limiting enzyme in heme degradation.

Animals↗
PubMed1992

The effect of enzyme induction on the cytochrome P450-mediated bioactivation of carbamazepine by mouse liver microsomes.

Predisposition to idiosyncratic toxicity with carbamazepine is thought to be due to a deficiency of the detoxication enzyme, microsomal epoxide hydrolase, although in some cases, concurrent administration of enzyme inducers might be a contributory risk factor, by altering the critical balance between bioactivation and detoxication. In this study, a mouse model has been used to determine the factors affecting carbamazepine bioactivation, using covalent binding and cytotoxicity as markers of bioactivation in vitro. Microsomes prepared from mice pre-treated with phenobarbitone increased (relative to the control microsomes) the formation of cytotoxic (12.3% vs 3.2%), protein-reactive (3.0% vs 2.0%) and stable (33.8% vs 18.1%) metabolites of carbamazepine. Similarly, pre-treatment with dexamethasone also increased the formation of the cytotoxic (24.8% vs 6.7%), protein-reactive (2.8% vs 1.5%) and stable (38% vs 19.8%) metabolites of carbamazepine, while beta-naphthoflavone pretreatment did not increase the formation of either the toxic or stable metabolites of carbamazepine when compared with its control microsomes. Co-incubation with gestodene (10-250 microM) resulted in a dose-dependent inhibition of both the bioactivation of carbamazepine and the formation of its stable 10,11-epoxide. SDS-PAGE and immunoblotting of the microsomes with anti-CYP3A antibody revealed the presence of a 52 kDa protein band in each preparation of microsomes, but the relative intensities of the bands, as measured by laser densitometry, were highest with the phenobarbitone and dexamethasone microsomes. The microsomal oxidation of cortisol to 6 beta-hydroxycortisol was also enhanced by pretreatment of mice with phenobarbitone (6.5% vs 2.7%) and dexamethasone (8.2% vs 4.3%), but not beta-naphthoflavone (2.2% vs 1.6%), when compared with their respective control microsomes, and was inhibited (range 25-68% inhibition), with all the microsomes by gestodene (50 microM). Taken collectively, the data in this study demonstrate that in the mouse, induction of the CYP3A subfamily significantly increases carbamazepine bioactivation. It is likely that in humans inducers of the orthologous form of this enzyme, most notably anticonvulsants, may increase the bioactivation of carbamazepine.

Animals↗
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↗
PubMed1975

On the mechanism of inhibition of enzyme induction in Escherichia coli by distamycin A.

The mechanism of the interference of the antiviral antibiotic distamycin A with the bacterial cell has been investigated. Labelled distamycin A is firmly bound by E. coli cells and the binding process does not require metabolic energy as indicated by the use of inhibitors. The antibiotic does not induce gross alteration in the cell membrane but inhibits cyclic AMP accumulation in the cells exposed to a glucose-free medium. This inhibition is concomitant with that exerted on the synthesis of an inducible enzyme such as beta-galactosidase. By the method of pulse induction it appears that distamycin A exterts its inhibiting effect on inducible synthesis at the level of transcription. This effect is probably related to an interference with the positive control of enzyme synthesis performed via the system represented by cyclic AMP and the CRP protein.

Binding Sites↗