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PubMed1989

Improved detection of beta-lactamase activity in isolates of Staphylococcus saprophyticus with the use of a modified Cefinase disk procedure.

The Cefinase disk (BBL Microbiology Systems, Cockeysville, MD) technique has been reported to be relatively insensitive for detection of beta-lactamase production by Staphylococcus saprophyticus. The effects of time (up to 24 hours) and temperature (25 degrees C vs. 35 degrees C) of test incubation as well as enzyme induction on Cefinase detection of beta-lactamase activity in clinical isolates of S. saprophyticus was investigated. Results were compared to beta-lactamase detection with the use of conventional nitrocefin and cloverleaf methods and with penicillin minimal inhibitory concentrations (MICs). Of 85 S. saprophyticus isolates, 84 (98.8%) had penicillin MIC end points of greater than or equal to 0.25 microgram/mL. Beta-lactamase was detected by at least one method in 73 (85.9%) of the isolates: 63 (74.1%) by nitrocefin, 55 (64.7%) by cloverleaf, and 63 (74.1%) by Cefinase. Of Cefinase-positive isolates, 56 (88.9%) and 63 (100%) were detected at 25 degrees C and 35 degrees C, respectively, and none required enzyme induction. At 35 degrees C, 4 (6.3%) and 19 (30.2%) of the Cefinase-positive isolates were detected at 1 hour and 24 hours, respectively. Incubation of Cefinase tests at 35 degrees C for 24 hours provides a satisfactory alternative to the conventional nitrocefin assay for detection of beta-lactamase activity in S. saprophyticus.

Cephalosporins↗
PubMed1991

Spermidine N1-acetyltransferase activity in rat uterus after 17 beta-estradiol and during the estrous cycle.

The administration of 17 beta-estradiol to ovariectomized rats stimulated in uterus the activity of spermidine N1-acetyltransferase, the rate-limiting enzyme in the polyamine interconversion pathway. Such a stimulation was largely prevented by cycloheximide and actinomycin D, which indicates that it was due to an enzyme induction. During the estrous cycle, uterine enzyme activity was highest at proestrus and lowest at estrus, when estrogen plasma levels are known to be high and low, respectively. The induction of the enzyme was associated with the appearance or an increase in N1-acetylspermidine in uterus. The results suggest that estrogens regulate spermidine N1-acetyltransferase activity in uterus.

Acetyltransferases↗
PubMed1994

Induction of Enzymes Associated with Lysigenous Aerenchyma Formation in Roots of Zea mays during Hypoxia or Nitrogen Starvation.

Either hypoxia, which stimulates ethylene biosynthesis, or temporary N starvation, which depresses ethylene production, leads to formation of aerenchyma in maize (Zea mays L.) adventitious roots by extensive lysis of cortical cells. We studied the activity of enzymes closely involved in either ethylene formation (1-amino-cyclopropane-1-carboxylic acid synthase [ACC synthase]) or cell-wall dissolution (cellulase). Activity of ACC synthase was stimulated in the apical zone of intact roots by hypoxia, but not by anoxia or N starvation. However, N starvation, as well as hypoxia, did enhance cellulase activity in the apical zone, but not in the older zones of the same roots. Cellulase activity did not increase during hypoxia or N starvation in the presence of aminoethoxyvinylglycine, an inhibitor of ACC synthase, but this inhibition of cellulase induction was reversed during simultaneous exposure to exogenous ethylene. Together these results indicate both the role of ethylene in signaling cell lysis in response to two distinct environmental factors and the significance of hypoxia rather than anoxia in stimulation of ethylene biosynthesis in maize roots.

Journal Article↗
PubMed1980

Vitamin D metabolism in patients treated with phenytoin and phenobarbitone.

There are many reports of abnormalities in calcium metabolism and even of frank osteomalacia in patients taking anticonvulsant drugs. Although enzyme induction has been suggested to be the cause of increased requirements for vitamin D leading to these changes, this has still to be proved. We have studied the metabolism of [3H]cholecalciferol and 25-hydroxycholecalciferol in subjects taking anticonvulsant drugs. The rate of removal of cholecalciferol from the plasma was no different from that in control subjects and no abnormality was detected in the production of disappearance of 25-hydroxycholecalciferol. However, plasma concentrations of 25-hydroxycholecalciferol fell more rapidly during the winter in epileptic subjects than in control subjects. Our results do not confirm that these changes are due to enzyme induction.

Calcifediol↗
PubMed2001

Drug interactions with the taxanes: clinical implications.

BACKGROUND: The taxanes paclitaxel and docetaxel are among the most active antitumor agents. Clinically important pharmacodynamic interactions have been reported to occur with these agents that are sequence or schedule dependent. Because the taxanes undergo hepatic oxidation via the cytochrome P450 system, pharmacokinetic interactions due to enzyme induction or inhibition can also occur. METHODS: A comprehensive literature search was conducted using Medline to identify clinically important drug-interactions with the taxanes. RESULTS: Clinically significant taxane interactions were identified for carboplatin, cisplatin, doxorubicin, docetaxel, epirubicin and anticonvulsants. Doxorubicin and epirubicin should be administered 24 h before paclitaxel, and the cumulative anthracycline dose limited to 360 mg/m(2). This will prevent the enhanced toxicities due to sequence and schedule dependent interactions between anthracyclines and paclitaxel. Conversely, paclitaxel should be administered at least 24 h before cisplatin to avoid a decrease in clearance and increase in myelosuppression. With concurrent anticonvulsant therapy, cytochrome p450 enzyme induction results in decreased paclitaxel plasma steady state concentrations, possibly requiring an increased dose of paclitaxel. A number of other drug interactions have been reported in preliminary studies for which clinical significance has yet to be established. CONCLUSION: Clinically significant drug interactions have been reported to occur when paclitaxel is administered with doxorubicin, cisplatin, or anticonvulsants (phenytoin, carbamazepine, and phenobarbital).

Anticonvulsants↗
PubMed1996

Expression of Ad4-BP/cytochrome P450 side chain cleavage enzyme and induction of cell death in long-term cultures of human granulosa cells.

Freshly isolated granulosa cells obtained from women undergoing in-vitro fertilization (IVF) become refractory to further gonadotrophin stimulation in culture due to their previous hormonal treatment. However, when precultured for 7 days in gonadotrophin-free medium they regain their response to both human chorionic gonadotrophin (HCG) and follicle stimulating hormone (FSH) with a 10-fold and 5-fold increase in progesterone production respectively, within an additional 7 days of culture. Forskolin, a direct activator of adenylate cyclase, increased progesterone levels 12-fold compared with non-stimulated cultures. Oestradiol formation was also significantly elevated (P < 0.005) following 48 h stimulation with luteinizing hormone (LH), FSH or forskolin. Intracellular cAMP levels rose 1.5-fold, 10-fold and 15-fold after 1 h of FSH, HCG or forskolin treatment. Expression of both cytochrome P450 side chain cleavage enzyme (SCC) and the steroidogenic transcription factor SF1/Ad4BP could be demonstrated by Western blotting. However, elevation of P450 SCC alone was evident following FSH and HCG stimulation. In the presence of serum, the ultrastructure of these cultured cells displayed numerous lipid droplets and well-developed mitochondria, characteristic of highly steroidogenic cells. The proportion of apoptotic nuclei in these cultures was < 30%. Removal of the serum increased apoptotic incidence to 40%, whereas addition of FSH prevented cell death significantly (P < 0.01). HCG and forskolin increased apoptosis to approximately 50%, while treatment with 8Br-cAMP led to 80% cell death. Our data suggest that, after prolonged culture, human granulosa cells can regain cAMP and steroidogenic response to gonadotrophin stimulation. Moreover, our experiments indicate that apoptosis and steroidogenesis can coexist in the same cell population while the interrelationship between these processes can be determined by the intracellular levels of cAMP.

Apoptosis↗
PubMed1977

A survey of drug interaction.

A survey is presented of the interaction phenomena between two or more simultaneously used drugs. The well known mechanisms of drug interaction, like chemical incompatibility, displacement of protein binding, enzyme induction, etc., are summarized and illustrated by means of practically relevant examples. Attention is paid to the fact that drug interaction can sometimes be advantageous from the clinical point of view, although in many cases it is an unwanted phenomenon in practical pharmacotherapy. Furthermore, the predictability and detection of interaction phenomena are mentioned briefly, together with the possibilities of distributing appropriate information to physicians and pharmacists.

Antacids↗
PubMed2004

Modulation of cytochrome P450 1A1 by food-derived heterocyclic aromatic amines.

A short-term effect of a meal of fried meat is a postprandial induction of hepatic and intestinal cytochrome P450 activity. In order to identify the components responsible for this effect we investigated the potency of food derived genotoxic heterocyclic aromatic amines (HA) to induce CYP1A1 in vitro. In two cell lines, the rat hepatoma cell line H4IIE and the human breast cancer cell line MCF-7, we investigated 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAC), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and Harman representing the different classes of HA at concentrations from 10(-8) to 10(-4) M. Induction of CYP1A1 was analysed on the mRNA level by semi-quantitative RT-PCR and the protein level (western blot using specific antibodies). The relative order of enzyme induction was Trp-P-1 with 1.4 x 10(-6) M (EC50 compared to TCDD 10(-9) M), MeAalphaC (1.4 x 10(-5)), Harman (2.1 x 10(-4)) and MeIQx (1.0 x 10(-3)). Furthermore, CYP1A1 enzyme activity was analysed as ethoxyresorufin-O-deethylase. While protein and mRNA analyses gave similar results, competitive inhibition impaired the enzyme activity assay. Inhibition of CYP1A1 activity was determined using microsomes of heterologous expressed CYP1A1. This dose-dependent inhibitory activity paralleled the induction potency. These results compare well with earlier data published for hepatic enzyme induction by HA observed in animal experiments. However, since the observed activities are rather weak and the amounts of HA ingested with a meal are low, there may be other factors involved in the observed postprandial enzyme induction in humans. On the other hand, concentrations in the micromolar range that are reached in high dosage animal experiments with HA may well influence cytochrome activity and, thus, influence the experimental outcome of these studies.

Amines↗
PubMed2005

Biomarker measurements in a coastal fish-eating population environmentally exposed to organochlorines.

The Lower North Shore region of the St. Lawrence River is home to a fish-eating population that displays an unusually high body burden of several organochlorines, including polychlorinated biphenyls (PCBs) and dioxin-like compounds (DLCs). We measured biomarkers indicative of liver enzyme induction and investigated the relationship with organochlorine body burden in adult volunteers from this population. We determined plasma concentrations of PCBs and chlorinated pesticides by high-resolution gas chromatography (HRGC) with electron capture detection. DLC concentrations were measured by the dioxin-receptor chemically activated luciferase expression (DR-CALUX) assay and in a subset of participants, by HRGC/high-resolution mass spectrometry. We measured cotinine, d-glucaric acid, and porphyrins in morning urine samples and determined liver CYP1A2 activity in vivo using the caffeine breath test. Neither DLC concentrations as measured by the DR-CALUX nor PCB-153 concentrations, the latter representing total PCB exposure, were correlated with biomarkers of effects. Smoking (morning urinary cotinine concentration) was positively related to CYP1A2 activity as measured by the caffeine breath test (p < 0.01). Liver CYP1A2 activity was in turn negatively correlated with PCB-105:PCB-153 and PCB-118:PCB-153 congener ratios (p < 0.05). Hence, despite the relatively high body burden of PCBs and DLCs in this population, only smoking had a significant correlation with biomarkers of hepatic enzyme induction. Our data are consistent with smoking-induced liver CYP1A2 activity altering heme metabolism and increasing the biotransformation of mono-ortho PCB congeners.

Biomarkers↗
PubMed1994

The mechanism of dioxin toxicity: relationship to risk assessment.

Risk characterization involves hazard identification, determination of dose-response relationships, and exposure assessment. Improvement of the risk assessment process requires inclusion of the best available science. Recent findings in the area of dioxin toxicity have led to a major effort to reassess its risk. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), commonly referred to as "dioxin," is the most toxic member of a class of related chemicals including the polyhalogenated dibenzo-p-dioxins, dibenzofurans, biphenyls, naphthalenes, azo- and azoxy-benzenes, whose toxicities can be expressed as fractional equivalencies of TCDD. These chemicals exert their effects through interaction with a specific intracellular protein, the Ah receptor. While binding to the receptor is necessary, it is not sufficient to bring about a chain of events leading to various responses including enzyme induction, immunotoxicity, reproductive and endocrine effects, developmental toxicity, chloracne, tumor promotion, etc. Some of these responses appear to be linear at low doses. Immunotoxicity and effects on the reproductive system appear to be among the most sensitive responses. The Ah receptor functions as a transcriptional enhancer, interacting with a number of other regulatory proteins (heat shock proteins, kinases, translocases, DNA binding species). Interaction with specific base sequences in the DNA appear to be modulated by the presence of other growth factors, hormones and their receptors as well as other regulatory proteins. Thus, dioxin appears to function as a hormone, initiating a cascade of events that is dependent upon the environment of each cell and tissue. While Ah receptor variants exist, all vertebrates examined have demonstrated such a protein with similar numbers of receptors and binding affinity for TCDD. Most species respond similarly to dioxin and related compounds. While a given species may be an outlier for a given response, it will behave like other animals for other responses. For both in vivo and in vitro end points where animal and human data exist, such as enzyme induction, chloracne, immunotoxicity, developmental toxicity, and cancer, the sensitivity of humans appears similar to that of experimental animals. Current levels of environmental exposure to this class of chemicals may be resulting in subtle responses in populations at special risk such as subsistence fisherman and the developing infant, as well as in the general population. Increased understanding of the mechanism of dioxin's effects as well as elucidation of exposure-dose relationships is leading to the development of a biologically based dose-response model in the ongoing process of incorporating the best science into the risk assessment of TCDD and related compounds.

Abnormalities, Drug-Induced↗
PubMed1988

Effects of chronic phenobarbital on verapamil disposition in humans.

Very little is known about the effects of hepatic enzyme induction with phenobarbital on the disposition of high clearance drugs in humans. Our study was undertaken to investigate the effect of phenobarbital on both alpha-1 acid glycoprotein concentrations and total and free verapamil and its metabolites. Single oral, single i.v., and multiple oral verapamil administrations were evaluated before and after 21 days of phenobarbital treatment in healthy caucasian male volunteers. Significant changes in the pharmacokinetics of total and free verapamil and its metabolites occurred in a predictable manner. Mean total apparent oral clearance after a single dose of verapamil was increased after phenobarbital treatment (75.1 +/- 49.2 vs. 376.2 +/- 221.8 ml/min/kg, P less than .05). Clearance of free drug increased to a similar magnitude. Mean total verapamil systemic clearance was increased (9.95 +/- 1.3 vs. 18.9 +/- 8.7 ml/min/kg, P less than .05); however free drug clearance was not altered. After multiple oral administration, total verapamil apparent oral clearance was increased after phenobarbital pretreatment (21.2 +/- 9.8 vs. 91.2 +/- 28.5 ml/min/kg, P less than .05). Free drug clearance was increased similarly. Finally, the pharmacokinetic theories derived for hepatic extraction of drugs subject to a high metabolic clearance can be successfully applied to men after liver enzyme induction with phenobarbital.

Adult↗
PubMed1999

Acarbose alone or in combination with ethanol potentiates the hepatotoxicity of carbon tetrachloride and acetaminophen in rats.

Acarbose reduces the absorption of monosaccharides derived from dietary carbohydrates, which play an important role in the metabolism and toxicity of some chemical compounds. We studied the effects of acarbose on the hepatotoxicity of carbon tetrachloride (CCl4) and acetaminophen (AP) in rats, both of which exert their toxic effects through bioactivation associated with cytochrome P450 2E1 (CYP2E1). Male Sprague-Dawley rats were kept on a daily ration (20 g) of powdered chow diet containing 0, 20, 40, or 80 mg/100 g of acarbose, with drinking water containing 0% or 10% of ethanol (vol/vol). Three weeks later, the rats were either killed for an in vitro metabolism study or challenged with 0.50 g/kg CCl4 orally or 0. 75 g/kg AP intraperitoneally. The ethanol increased the hepatic microsomal CYP2E1 level and the rate of dimethylnitrosamine (DMN) demethylation. The 40- or 80-mg/100 g acarbose diet, which alone increased the CYP2E1 level and the rate of DMN demethylation, augmented the enzyme induction by ethanol. The 40- or 80-mg/100 g acarbose diet alone potentiated CCl4 and AP hepatotoxicity, as evidenced by significantly increased levels of both alanine transaminase (ALT) and aspartate transaminase (AST) in the plasma of rats pretreated with acarbose. Ethanol alone also potentiated the toxicity of both chemicals. When the 40- or 80-mg/100 g acarbose diet was combined with ethanol, the ethanol-induced potentiation of CCl4 and AP hepatotoxicity was augmented. Our study demonstrated that high doses of acarbose, alone or in combination with ethanol, can potentiate CCl4 and AP hepatotoxicity in rats by inducing hepatic CYP2E1.

Acarbose↗
PubMedDate not supplied

Induction of hepatic and presystemic metabolism of antipyrine in the mice: rifampicin versus rifabutin.

The effects of hepatic and presystemic enzyme induction on the bioavailability (F) and disposition of antipyrine after repeated rifampicin (RFM) and rifabutin (RBT) exposure were studied in mice. ICR mice were divided to receive 4 daily oral dosing of either the dosing vehicle or 50 mg/kg of REM or RBT. At the completion of rifamycin dosing, the pharmacokinetics of antipyrine were assessed following either a single 50 mg/kg oral dose or a 20 mg/kg intravenous dose. Blood samples were collected (n=4/timepoint) over a 6 h period. The content of P450 in the liver and small intestine (GI) was also assessed in parallel. Systemic antipyrine clearance (CL) increased from 31.8 ml/min/kg (controls) by 64% and 42% following repeated exposure to RFM and RBT, respectively. Estimate of F for antipyrine decreased from 0.97 in controls to 0.58 and 0.82 in animals treated with RFM and RBT, respectively. The content of P450 (nmol/mg protein) in the liver increased from 0.61 (control) to 1.36 following RFM and 0.82 for RBT, while no significant changes were observed for the GI tract. The i.v. dosing data confirmed the induction of antipyrine metabolism in the liver by both rifamycins yet the induction potential was approximately 1/3 lower for RBT. This difference was consistent with the changes observed in the hepatic P450 protein content, but this alone could not account for the reduction in the F for antipyrine. Therefore, predictions for changes in F of an interacting agent should not be judged solely on the basis of the metabolic status of the liver. The relative contribution of metabolic induction and presystemic drug loss to bioavailability/absorption should also be further delineated for its relevance to poly-pharmacy in patients likely to receive long-term rifamycin based treatment.

Administration, Oral↗
PubMed1989

Influence of rifampin on tocainide pharmacokinetics in humans.

The effects of metabolic enzyme induction by rifampin on the pharmacokinetics of tocainide were studied in eight healthy volunteers. In an open, unrandomized fashion, volunteers received tocainide hydrochloride 600 mg orally. Blood samples were obtained immediately before and at various time intervals up to 48 hours after the dose. Urine samples were collected before and at various intervals up to 72 hours after the dose. Serum and urine samples were assayed for tocainide content by high-performance liquid chromatography. After a four-week washout period, volunteers ingested 300 mg of rifampin by mouth every 12 hours. After 10 doses, subjects received a second oral dose of tocainide hydrochloride 600 mg, and blood and urine samples were collected as before. During the sampling period, subjects continued to ingest rifampin 300 mg orally every 12 hours. Significant differences in elimination rate constant (average increase, 0.0545 to 0.0748 hr-1), elimination half-life (average reduction, 13.2 to 9.4 hours), oral clearance, and area under the concentration-time curve (average reduction, 76.8 to 55.0 mg.hr/L) between the control and rifampin treatment phases were observed. Volume of distribution and renal clearance of tocainide were not significantly different after rifampin treatment. Tocainide appears to be susceptible to significant drug-drug interactions mediated by metabolic enzyme induction.

Adult↗
PubMedDate not supplied

Polychlorinated biphenyl (PCB) and dichlorodiphenyl dichloroethylene (DDE) exposure among Native American men from contaminated Great Lakes fish and wildlife.

The New York State Department of Health is performing an investigation of Mohawk men, women, and infants who live at the Akwesasne Reserve along the St. Lawrence River in New York, Ontario, and Quebec Three large industrial facilities bordering the Akwesasne Reserve have seriously contaminated the soil and the sediments and fish of the adjacent St. Lawrence River with polychlorinated biphenyls (PCBs). The main study goals are to investigate the associations among the consumption of locally caught fish, residential exposure, body burdens of PCBs, and liver enzyme induction. Contamination with PCBs, polychlorinated dibenzofurans, polychlorinated dibenzodioxins, polyaromatic hydrocarbons, dichlorodiphenyl dichloroethylene (DDE) and other chemicals has been documented in locally caught fish, ducks, and other wildlife. The contamination of fish and wildlife is a major concern of the Mohawk people, since their tradition and culture emphasize the interdependence of man and his environment and because many residents formerly depended heavily on local fish and waterfowl for food. The focus of this research from 1986-1992 was on nursing women and infants. The major purpose of the current project is to determine if there are associations between dietary, residential, and occupational exposures to PCBs and DDE and individual body burdens in Mohawk men, specifically the husbands, partners, fathers, brothers, or other male relatives of the women in our other studies. In other fish-eating populations, adult men have tended to demonstrate higher PCB and DDE body burdens than women and children. Exposure estimates based on the reported consumption of locally caught fish and wildlife and residential histories will be correlated with the specific pattern of PCB congeners found in serum, thereby establishing a direct relationship between two potential sources of exposure and body burdens. Liver function will be examined through the caffeine breath test (CBT), a sensitive, noninvasive method of assessment of enzyme induction, one of the earliest detectable biological responses to PCBs in laboratory animals. This test appears promising as a method to detect subtle subclinical effects before the onset of overt clinical symptoms. The project is among the first to explore differences in dietary and other exposures, body burdens, and potential adverse health effects due to specific PCB congeners in men and women from the same source population.

Animals↗
PubMed1999

Role of cytochrome P4501A in biotransformation of the potential anticancer drug oracin.

Metabolic fate of the potential anticancer drug oracin (I), was studied at microsomal level in rat using enzyme induction and inhibition. One of the main metabolites arising during incubation of hepatic microsomal fraction with oracin is 3-hydroxyoracin (III). Cytochromes P450 non-specific inhibitors (carbon monoxide, aminobenzotriazole, 1-benzylimidazole, proadifen hydrochloride, n-octylamine) diminished amount of III. Among several specific inducers of rat cytochromes P450 isoforms used, only 3-methylcholanthrene, inducer of cytochrome P4501A, caused a significant stimulation of 3-hydroxyoracin production. The amount of III was decreased to the level of controls when the microsomes prepared from 3-methylcholanthrene treated rats were incubated with substrate in the presence of specific P4501A inhibitor alpha-naphthoflavone. From the above mentioned results we can assume that metabolite III is formed from oracin by cytochrome P450 belonging to subfamily 1A.

Aniline Hydroxylase↗
PubMed1988

In vivo kinetics and DNA-binding properties of the Ah receptor in the golden Syrian hamster.

The in vivo long-term cytosolic-nuclear kinetics and DNA-binding properties of the Ah receptor were examined in liver from the golden Syrian hamster. For the kinetic studies, a dose of [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin ([3H]TCDD) that has been previously shown to produce maximal and sustained hepatic enzyme induction without substantial toxicity was used. Following an intraperitoneal dose of 10 micrograms/kg of [3H]TCDD, occupied cytosolic receptor levels reached a peak within 8 h and then decreased rapidly to a level that was approximately 2% of the total receptor. Throughout the 35-day period, unoccupied cytosolic receptor represented from 65 to 80% of the total receptor content. At 8 h following dosing, less than 30% of the total amount of receptor was associated with the nuclear fraction; this percentage declined slowly to less than 5% of the total at Day 35. The half-life for the decline in detectable nuclear receptor levels was 13 days and was similar to the half-life for the decline in [3H]TCDD content of the whole liver, cytosol, and nuclear extract. The Ah receptor contained in hamster hepatic cytosol underwent a ligand-dependent transformation in vitro to two forms having affinity for DNA-Sepharose, one of which was isolated from nuclei of animals treated with [3H]TCDD in vivo. A comparison of the specific binding recovered following various analytical procedures revealed that the binding of [3H]TCDD to the form not found in nuclear extracts was more labile under certain experimental conditions. These studies indicate the heterogeneity of the Ah receptor in hamster hepatic cytosol and suggest that DNA binding in vitro and nuclear uptake in vivo occur through a ligand-dependent transformation process. The maintenance of maximal hepatic enzyme induction is, in part, a consequence of the sustained presence in the nucleus of only a small percentage of the total receptor content. The whole-tissue kinetics of TCDD appears to be a major factor regulating the long-term retention of the TCDD-receptor complex in the nucleus.

Animals↗
PubMed2003

Effect of pretreatment of cytochrome P450 (P450) modifiers on neurobehavioral toxicity induced by deltamethrin.

To investigate the involvement of cytochrome P450 (P450) enzyme induction and the effect of different P450 modifiers in the neurobehavioral toxicity of deltamethrin, deltamethrin (10 mg/kg; orally for 1 day) was administered to young male albino Wistar rats, or in rats pretreated with phenobarbital (PB; 80 mg/kg, ip for 5 days), an inducer of P450 2B1/2B2 or 3-methylcholanthrene (MC; 30 mg/kg, ip for 5 days), an inducer of P450 1A1/1A2 or cobalt chloride (CoCl(2); sc for 2 days), a depletor of P450s. The administration of PB or MC or CoCl(2) alone did not produced any symptoms of neurobehavioral toxicity. While a single oral administration of deltamethrin produced tremors in two out of 10 rats and decreased the spontaneous locomotor activity, pretreatment with MC or PB potentiated the deltamethrin induced neurobehavioral toxicity with 50% of the treated rats exhibiting tremors. Half of the animals pretreated with MC prior to exposure to deltamethrin also exhibited choreoathetosis. The decrease in the spontaneous locomotor activity was found to be much more significant in PB- or MC-pretreated animals exposed to deltamethrin. In contrast to the pretreatment with inducers, rats pretreated with CoCl(2) exhibited no symptoms of tremors or choreoathetosis, indicating that a reactive metabolite of deltamethrin is formed by P450 catalysed reactions which is involved in the neurobehavioral toxicity of deltamethrin.

Animals↗