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PubMed1980

Biochemical evidence for osteomalacia with carbamazepine therapy.

Many anticonvulsants are known to cause osteomalacia, however, carbamazepine has not previously been studied in this regard. We studied 31 patients on carbamazepine (mean dose 758 mg +/- s.d. 468 mg per day), as a single drug for epilepsy for a duration of 20.5 +/- 10 months. Three patients (10%) had hypocalcaemia, and serum calcium was significantly lower (P less than 0.01), and serum alkaline phosphatase significantly higher (P less than 0.05) than matched control subjects. Serum phosphorus was significantly inversely correlated and serum alkaline phosphatase was positively correlated with both dose and duration, but not blood levels of carbamazepine. These findings are consistent with mild biochemical changes of osteomalacia. None of the patients were symptomatic. Serum bilirubin (mean 2.6 +/- 1.4 mumol/l) was very significantly lower (P less than 0.01) than in controls. Both the calcium and bilirubin disturbances are probably due to carbamazepine causing hepatic microsomal enzyme induction.

Adolescent↗
PubMed1977

[Hyperamylasemia following infusion of hydroxyethyl starch with different molecular weight distributions].

The infusion of hydroxyethyl-starch leads to hyperamylasemia due to the complex structural interrelation of the amylase molecules in the serum and the hydroxyethyl-starch molecules. The amylase clearance is reduced because glomerular filtration of the macromolecules thus formed is not possible. The extent of hyperamylasemia is dependent on the intravascular remission duration of the hydroxyethyl-starch preparation used. The question, whether and to what extent an enzyme induction in the liver also contributes to the observed hyperamylasemia, remains open.

Alkaline Phosphatase↗
PubMed2004

Possible induction of cholinesterase in epileptic patients treated with anticonvulsant drugs: relationship with lipoprotein levels.

The effect of enzyme-inducing anticonvulsant drugs on the serum concentrations of lipoproteins has been widely studied. However, there is little agreement between the results with regard to the possible development of a lipoprotein profile related to an increased or decreased cardiovascular risk. It has been suggested that cholinesterase (ChE) could be induced by these drugs, something of undeniable interest as ChE appears to have a relation to the metabolism of lipoproteins. The serum activity of ChE was determined in a group of 90 adult epileptic patients (56 male and 34 female) treated with phenobarbital, phenytoin, and carbamazepine. The liver enzyme induction produced by these drugs was then evaluated by determining serum gamma-glutamyltranspherase activity and urinary excretion of D-glucaric acid. A significant increase of serum ChE (p < 0.005) was found in the group of patients compared to a control group (n = 49) with a similar distribution for age and sex. A significant correlation was found for both male and female patients between ChE and concentrations of triglycerides, phospholipids, cholesterol, low-density lipoprotein (LDL) phospholipids, LDL-cholesterol, and apolipoprotein B (p < 0.01). Similarly, in female patients, ChE had a significant correlation with the total cholesterol/high-density lipoprotein (HDL) cholesterol and LDL-cholesterol/HDL-cholesterol ratios (p < 0.01). The ChE/HDL-cholesterol relationship, which has been proposed as a marker for cardiovascular risk, presented significant correlations with the total cholesterol/HDL-cholesterol and LDL-cholesterol/HDL-cholesterol ratios in patients of both sexes (p < 0.001). In the case of epileptic patients treated with enzyme-inducing anticonvulsant drugs, there may be an association between the possible induction of ChE and the metabolism of lipoproteins containing apolipoprotein B.

Adolescent↗
PubMed1991

DNA damage induced by 7,12-dimethylbenz[a]anthracene in the liver and the mammary gland of rats exposed to polycyclic aromatic hydrocarbon enzyme inducers during perinatal life.

The long-lasting modulating effect induced by the prenatal or neonatal exposure to phenobarbital (PB) and aroclor on the genotoxic activity of 7,12-dimethylbenz[a]anthracene (DMBA) in female Sprague-Dawley rats was studied. The effect was measured as DNA damage evaluated in the liver and in the mammary gland of 55-day-old animals, 4 and 24 h after an i.g. injection of 80 mg/kg of DMBA. PB was given per os, i.g. or in drinking water to pregnant females and by i.g. only to neonates or in adult progeny. Aroclor was injected i.g. in prenatal and in neonatal life, and a second dose was given in adult life. Under these experimental conditions it was shown that DNA damage kinetics caused by DMBA are modulated by exposure to PB and, to a minor extent, by aroclor. The amount and persistence of DNA damage were highest when PB was administered to neonates. An average 2-fold increase in the elution constants (K) of DNA in the liver and the mammary gland was observed 4 h after DMBA treatment, as compared to uninduced animals. Repeated enzyme induction by PB seems to reduce DMBA genotoxicity, as shown by a decrease in DNA damage and persistence in the liver and mammary gland. The inducibility of the monooxygenase enzyme system in perinatal life favouring metabolic activation or inactivation of polycyclic aromatic hydrocarbons might be critical in determining individual susceptibility of adult progeny to chemical carcinogenesis by DMBA.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2006

Induction of cytochrome P450: assessment in an immortalized human hepatocyte cell line (Fa2N4) using a novel higher throughput cocktail assay.

Over recent years the application of cocktail studies to measure biological markers has become increasingly popular. The current study investigated a novel approach in assessing cytochrome P450 (P450) enzyme induction in an immortalized cell line using a cocktail of five P450 substrate probes compared with the traditional single-probe approach. The findings reported herein support use of a cocktail approach to assess the induction of the major P450s, namely, CYP3A4, CYP1A2, and CYP2C9. CYP2C19 and CYP2D6 could also be followed as part of the cocktail approach reported. Response to prototypical inducers did not differ to those observed in the presence of the specific probes alone. Consequently, this approach requires significantly fewer sample numbers if screening the induction potential of more than one P450. Moreover, these studies highlight the utility of the immortalized cell line Fa2N4 as a robust model system for induction studies. In conclusion, the current experimental setup is an improvement on current approaches used to assess P450 induction, significantly increasing sample throughput.

Aryl Hydrocarbon Hydroxylases↗
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↗
PubMed1986

Effects of putrescine on synthesis and degradation of ornithine decarboxylase in primary cultured hepatocytes.

Changes in both synthesis rate and degradation rate of ornithine decarboxylase (ODC) were pursued in primary cultures of adult rat hepatocytes during the process of ODC induction caused by asparagine and glucagon and also during the process of rapid ODC decay caused by putrescine. The synthesis rate of ODC was determined by [35S]methionine incorporation into the enzyme, which was separated afterwards by immunoprecipitation and sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. The degradation rate of ODC was determined by following the decay of prelabeled ODC. The enzyme induction caused by asparagine (10 mM) and glucagon (1 microM) was due both to an increase in the synthesis rate and to a decrease in the degradation rate. Addition of 10 mM putrescine caused a rapid decay of ODC activity, which was faster than ODC decay in the presence of cycloheximide. This rapid decay in ODC activity was accompanied by slightly slower decay in ODC protein, which was due both to partial suppression of ODC synthesis and to several fold acceleration of ODC degradation.

Animals↗
PubMed1986

LLC-PK1 cell mutants in cAMP metabolism respond normally to phorbol esters.

Mutants of the pig kidney cell line, LLC-PK1, affected in cAMP metabolism, were examined for cAMP-dependent protein kinase (cAMP-PK) activity and for cAMP-mediated induction of urokinase-type plasminogen activator (uPA). The FIB4 and FIB6 mutant cell lines possessed about 10% parental levels of cAMP-PK activity and concomitantly reduced uPA production (10-20% parental) in response to calcitonin, forskolin and 8-bromo cAMP. The FIB1, FIB2 and FIB5 mutant cell lines had about 70% parental levels of cAMP-PK and the synthesis of uPA was 40-60% parental. Thus, cAMP-mediated induction of uPA showed a dependence on the absolute levels of cAMP-PK. However, uPA synthesis in response to phorbol-12-myristate-13-acetate by all of the mutants was similar to parental, which indicates that enzyme induction mediated by phorbol esters does not involve cAMP or cAMP-PK.

Animals↗
PubMed1976

Microbial metabolism of alkylbenzene sulphonates. Variance in enzyme complement of a Bacillus in response to growth substrate.

Growth of a Bacillus species at the expense of an alkylbenzene sulphonate (ABS) synthetic detergent homologue (1-phenylundecane-p-sulphonate, 11-ABS) containing an odd number of carbon atoms in the alkyl side chain induced an enzyme complement able to biodegrade 11-ABS by alkyl side-chain oxidation, and "ortho cleavage" aromatic-ring oxidation reactions. Growth of the Bacillus at the expense of an ABS homologue containing an even number of carbon atoms in the alkyl side chain (1-phenyldodecane-p-sulphonate, 12-ABS) induced an enzyme complement able to biodegrade 12-ABS by alkyl side-chain oxidation, and "meta cleavage" aromatic-ring oxidation reactions. The results of a number of different growth and enzyme induction experiments confirm that both 11-ABS and 12-ABS are initially biodegraded by an identical complement of enzymes catalysing the alkyl-side-chain oxidation reactions, but that the subsequent metabolism of the aromatic moieties remaining after the removal of the alkyl side chain from 11-ABS and 12-ABS occurs by two separate pathways requiring the de novo induction of different substrate-specific enzyme complements. The detection of the predicted changes in enzyme complement subsequent to changes in the growth substrate of the Bacillus provide confirmation of the biodegradation pathways operating in the microorganism.

4-Hydroxybenzoate-3-Monooxygenase↗
PubMed1982

Synergistic induction of alkaline phosphatase in colonic carcinoma cells by sodium butyrate and hyperosmolality.

Exposing HT-29 cells to the combination of two inducers of intestinal alkaline phosphatase, sodium butyrate and hyperosmolality, causes a synergistic (over 1000-fold) increase in specific activity. Evidence is presented showing that enzyme induction is reversible; the half-life of the induced activity is approximately 30 h. Preinduction by butyrate or by hyperosmolality does not prime the cells so as to respond synergistically when subsequently exposed to hyperosmolality or butyrate, respectively. This study demonstrates that when applied in combination, the effect on gene expression by one alkaline phosphatase inducer is amplified by the other.

Adenocarcinoma↗
PubMed1980

Enhancement by streptozotocin and N-methyl-N'-nitro-N-nitrosoguanidine of the tyrosine aminotransferase activity in cultured rat liver cells: role of dexamethasone and NAD.

The activity of tyrosine aminotransferase (TAT) (EC 2.6.1.5) was enhanced 3-fold after a 5-h exposure of cultured rat liver cells (RLC) to streptozotocin (SZ) at concentrations higher than 100 microgram/ml (0.38 mM) in the presence of 10 nM dexamethasone, a potent glucocorticoid inducer for the enzyme. The structurally related carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) also enhanced the aminotransferase in the presence of the glucocorticoid, but its optimal concentration was at 100 ng/ml (0.68 microM). While the cellular NAD (NAD+ + NADH) concentration was reduced to 60% of the control levels, the rate of poly(ADP-ribose) formation in the isolated cell nuclei was unaffected by treating the cells with SZ. The enhancement of tyrosine aminotransferase by SZ and MNNG was effectively prevented by nicotinamide. Using nicotinamide and its derivatives such as 1-methyl-, N'-methyl- or 6-amino-derivatives it was found that the degree of enzyme induction is almost inversely proportional to the cellular NAD content, though the activity of nuclear poly(ADP-ribose)polymerase remains unchanged. The results indicate that SZ or MNNG, in combination with dexamethasone, stimulate the induction of tyrosine aminotransferase through their NAD lowering action.

Animals↗
PubMed1978

A new procedure for the visualization of multiple forms of gamma-glutamyl transferase (GGT). Results in normals, patients receiving enzyme-inducing drugs and patients having liver parenchymal lesions.

The activity of gamma-glutamyl transferase (GGT, EC 2.3.2.2) in sera of 68 healthy individuals, of 38 patients receiving anti-epileptic drugs, and of 27 patients having liver parenchymal lesions, was visualized after electrophoresis on cellulose-acetate gel using the substrate gamma-L-glutamyl-p-nitroanilide as a new colour reagent. The liberated p-nitroaniline was converted in situ into a lilac-coloured product using the Bratton-Marshall reaction. In most samples two bands were demonstrated, one located between albumin and alpha1-globulin, called GGT 1, the other located in the alpha2-globulin region, GGT 2. In a few samples a third band, GGT 3, with far less activity than the other bands, occurred in the beta-globulin region. When it occurred, an increase in total GGT activity was mainly due to an increase of GGT-1 activity. The possible role of the determination of GGT-1 activity as a monitor of microsomal enzyme induction is discussed.

Adolescent↗
PubMed1986

GAL3 gene product is required for maintenance of the induced state of the GAL cluster genes in Saccharomyces cerevisiae.

The activities of the first three enzymes for galactose catabolism normally become detectable within 15 min after the addition of galactose into a culture of the yeast Saccharomyces cerevisiae. In S. cerevisiae with a recessive mutation termed gal3, a longer-than-normal lag is observed before the appearance of the enzyme activities (O. Winge and C. Roberts, C. R. Trav. Lab. Carlsberg Ser. Physiol. 24:263-315, 1948). I isolated two S. cerevisiae mutants with temperature-sensitive defects in the GAL3 gene. Temperature shift experiments with one of those mutants led to the conclusion that the GAL3 function is required not only for the initiation of enzyme induction but also for the maintenance of the induced state in galactose-nonfermenting S. cerevisiae because of a defect in any of the genes for the galactose-catabolizing enzymes, such as gal1 or gal10. In contrast, the GAL3 function is phenotypically dispensable in galactose-metabolizing S. cerevisiae. Thus, the normal catabolism of galactose can substitute for the GAL3 function.

Enzyme Induction↗
PubMed1998

A mechanistic approach to antiepileptic drug interactions.

OBJECTIVE: To describe the primary types of antiepileptic drug (AED) interactions by using a mechanistic approach. DATA SOURCES: A literature search was performed using MEDLINE and bibliographies of recent review articles and published abstracts. DISCUSSION: AEDs are associated with a wide range of drug interactions, including hepatic enzyme induction and inhibition and protein-binding displacement. Hepatic induction by AEDs affects the metabolism of a limited number of drugs with low therapeutic indices. Anticipation of induction interactions and careful clinical monitoring may alleviate potential problems. Most commonly used AEDs are eliminated through hepatic metabolism catalyzed by the cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) enzymes. Phenytoin, phenobarbital, and carbamazepine induce CYP and UGT enzymes. Lamotrigine is a weak inducer of UGT. Valproate is a broad-spectrum inhibitor of UGT enzymes, epoxide hydrolase, and CYP2C enzymes. Felbamate induces CYP3A4, but inhibits CYP2C19 substrates. Topiramate inhibits only CYP2C19 substrates. Ethosuximide, gabapentin, tiagabine, and vigabatrin are neither inducers nor inhibitors of drug metabolism. Hepatic enzyme inhibition usually occurs because of competition at the enzyme site. Knowledge of the specific metabolic enzymes involved in the metabolism of AEDs allows clinicians to predict potential interactions. CONCLUSIONS: By understanding the mechanisms of drug interactions, the pharmacist can play a key role in patient care by anticipating and preventing AED drug interactions.

Acetates↗
PubMed1988

Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver.

Anticarcinogenic enzyme inducers are of two types: (a) bifunctional inducers [2,3,7,8-tetrachlorodibenzo-p-dioxin, polycyclic aromatics, azo dyes, beta-naphthoflavone] that elevate both Phase II enzymes [e.g., glutathione S-transferases, UDP-glucuronosyltransferases, and NAD(P)H:(quinone-acceptor) oxidoreductase] and certain Phase I enzymes [e.g., aryl hydrocarbon hydroxylase (AHH)]; and (b) monofunctional inducers [e.g., diphenols, thiocarbamates, 1,2-dithiol-3-thiones, isothiocyanates] that elevate primarily Phase II enzymes without significantly affecting AHH. Since Phase I enzymes such as AHH may activate precarcinogens to ultimate carcinogens whereas Phase II enzyme induction suffices to achieve chemoprotection, an understanding of the molecular mechanisms that regulate these enzymes is critical for devising methods for chemoprotection. We report a systematic analysis of the inductions of aryl hydrocarbon hydroxylase (AHH) and NAD(P)H:quinone reductase (QR) by seven monofunctional and eight bifunctional inducers, singly or in combination, in a murine hepatoma cell line (Hepa 1c1c7) and two mutants defective in either Ah (Aryl hydrocarbon) receptor function (BPrc1) or in AHH expression (c1). We have also examined such inductions in genetically defined mouse strains with high affinity (C57BL/6J) and low affinity (DBA/2J) Ah receptors. The combination of our earlier model for the induction of Phase I and Phase II enzymes (H. J. Prochaska, M. J. De Long, and P. Talalay, Proc. Natl. Acad. Sci. USA, 82: 8232, 1985) with mechanism(s) for autoregulation of AHH (O. Hankinson, R. D. Anderson, B. W. Birren, F. Sander, M. Negishi, and D. W. Nebert, J. Biol. Chem., 260: 1790, 1985) is compatible with our results. Thus, induction of QR by monofunctional inducers does not depend on a competent Ah receptor or AHH activity and appears to involve an electrophilic chemical signal. In contrast, bifunctional inducers require competent Ah receptors to induce both AHH and QR, although the latter process appears to be regulated by more than one mechanism. It is our view that bifunctional inducers bind to the Ah receptor thereby enhancing transcription of genes encoding both AHH and QR. Metabolizable bifunctional inducers are then converted by the induced AHH to products that resemble monofunctional inducers and are capable of generating the aforementioned chemical signal. The existence of mechanism(s) for AHH autoregulation that also affect Phase II enzyme expression would account for the high basal activities of QR in the AHH-defective mutant (c1).

Animals↗
PubMed2005

P450 induction alters paclitaxel pharmacokinetics and tissue distribution with multiple dosing.

PURPOSE: Paclitaxel (Taxol) is an effective agent against a broad range of human cancers. Studies on the metabolism and disposition of paclitaxel have shown that it is primarily eliminated via hepatic metabolism by P450 enzymes (2C8 and 3A4) to essentially inactive metabolites, and that biliary and gut transport by P-glycoprotein (PGP) as well as urinary elimination of the parent compound play relatively minor roles. Recent studies in vitro have shown that paclitaxel treatment increases the level of CYP2C8 and CYP3A4 in human hepatocytes as well as PGP in colon tumor cells. The data suggest that previous paclitaxel exposure may influence metabolism and elimination of subsequent doses. Further, since weekly paclitaxel dose schedules are becoming more common as opposed to the original every 21-day dosing, the likelihood of enzyme induction from previous doses impacting that from subsequent doses is increased. METHODS: To study the potential for such sequence-dependent alterations in paclitaxel pharmacokinetics, we carried out pharmacokinetic studies in mouse plasma and tissues following day 1 and days 1 and 5 dosing at 20 mg/kg. Paclitaxel concentrations were determined by a sensitive LC/MS/MS assay out to 16 h post-dosing in plasma, liver, kidney, gut and heart. The effect of paclitaxel treatment on hepatic expression of PGP and P450 isoforms (CYP2C and CYP3A) was determined to elucidate the mechanism by which paclitaxel disposition is altered by previous drug exposure. RESULTS: Pharmacokinetic analysis of the data showed that plasma and tissue AUC values after treatment on day 5 following a dose on day 1 were between 50% and 74% of those determined following a single dose on day 1. The terminal elimination half-life was not different. Activity and protein levels for CYP2C in liver were elevated at 24 and 96 h after paclitaxel dosing. Cremophor EL, a carrier solvent for paclitaxel, also caused elevated CYP2C activity. Neither CYP3A nor PGP levels in liver were altered by paclitaxel or Cremophor EL treatment at the 24-h and 96-h time points. The levels of 6alpha-OH-paclitaxel in feces were increased on day 5 as opposed to day 1 while paclitaxel levels in feces were unchanged. CONCLUSIONS: The results of our studies showed that paclitaxel pharmacokinetics are altered by previous paclitaxel exposure up to 96 h earlier.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1982

Influence of Mycoplasma arginini infection on the induction of aryl hydrocarbon hydroxylase by TCDD in rat hepatoma cell cultures.

Mycoplasma arginini was eliminated from a rat hepatoma cell line (H-4-II-E) by plating at low cell density and treatment with chlortetracycline (250 micrograms/ml), kanamycin (250 micrograms/ml), tylosin (100 micrograms/ml), 3% M. arginini antiserum and 5% fresh guinea-pig serum. The induction of AHH activity in the cell culture was measured in response to increasing concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The ED50 values (estimated doses that produce 50% maximum enzyme induction) were calculated to be 0.256, 0.452 and 0.344 pmol TCDD/plate for original, mycoplasma-free and reinfected cells, respectively. Although the absence of M. arginini in the rat hepatoma cell line makes the cells slightly less responsive to AHH induction by TCDD, this decrease does not detract from the use of the method to screen food extracts and environmental samples for the presence of certain toxic planar organic compounds.

Animals↗