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Biomedical subjects

D Parmar

Publications and source records attributed to D Parmar.

At least 19 recordsLinked to original sources
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↗
PubMed2003

Effect of lindane on hepatic and brain cytochrome P450s and influence of P450 modulation in lindane induced neurotoxicity.

Oral administration of lindane (2.5, 5, 10 and 15 mg/kg, body weight) for 5 days was found to produce a dose-dependent increase in the activity of P450 dependent 7-ethoxyresorufin-O-deethylase (EROD), 7-pentoxyresorufin-O-dealkylase (PROD) and N-nitrosodimethylamine demethylase (NDMA-d) in rat brain and liver. A significant increase in the hepatic and brain P450 monooxygenases was also observed when the duration of exposure of low dose (2.5 mg/kg) of lindane was increased from 5 days to 15 or 21 days. As observed with different doses, the magnitude of induction in the activity of P450 monooxygenases was several fold higher in liver microsomes when compared with the brain. Western blotting studies have indicated that the increase in the P450 enzymes could be due to the increase in the expression of P450 1A1/1A2, 2B1/2B2 and 2E1 isoenzymes. In vitro studies using organic inhibitors specific for individual P450 isoenzymes and antibody inhibition experiments have further demonstrated that the increase in the activity of PROD, EROD and NDMA-d are due to the increase in the levels of P450 2B1/2B2, 1A1/1A2 and 2E1 isoenzymes, respectively. Induction studies have further shown that while pretreatment of 3-methylcholanthrene (MC), an inducer of P4501A1/1A2, did not produce any significant effect in the incidence of lindane induced convulsions, pretreatment with phenobarbital (PB), an inducer of P450 2B1/2B2 or ethanol, an inducer of P450 2E1 catalysed reactions, significantly increased the incidence of lindane induced convulsions. Similarly, when the P450-mediated metabolism of lindane was blocked by cobalt chloride incidence of convulsions was increased in animals treated with lindane indicating that lindane per se or its metabolites formed by PB or ethanol inducible P450 isoenzymes are involved in its neurobehavioral toxicity.

Administration, Oral↗
PubMed2002

Cytochrome P450 2E1 dependent catalytic activity and lipid peroxidation in rat blood lymphocytes.

To investigate the similarities in the catalytic activity of blood lymphocyte P450 2E1 in blood lymphocyte with the liver isoenzyme, NADPH dependent lipid peroxidation and activity of N-nitrosodimethyamine demethylase (NDMA-d) was studied in rat blood lymphocytes. Blood lymphocytes were found to catalyse NADPH dependent (basal) lipid peroxidation and demethylation of N-nitrosodimethylamine (NDMA). Pretreatment with ethanol or pyrazole or acetone resulted in significant increase in the NADPH dependent lipid peroxidation and the activity of NDMA-d in blood lymphocytes and liver microsomes. In vitro addition of CCl(4) to the blood lymphocytes isolated from control or ethanol pretreated rats resulted in an increase in the NADPH dependent lipid peroxidation. Significant inhibition of the basal and CCl(4) supported NADPH dependent lipid peroxidation and NDMA-d activity in blood lymphocytes isolated from control or ethanol pretreated rats by dimethyl formamide or dimethyl sulfoxide or hexane, solvents known to inhibit P450 2E1 catalysed reactions in liver and anti- P450 2E1, have indicated the role of P450 2E1 in the NADPH dependent lipid peroxidation in rat blood lymphocytes. The data indicating similarities in the NADPH dependent lipid peroxidation and NDMA-d activity in blood lymphocyte with the liver microsome have provided evidence that blood lymphocyte P450 2E1 could be used as a surrogate to monitor and predict hepatic levels of the enzyme.

Acetone↗
PubMed2002

Antistress effects of bacosides of Bacopa monnieri: modulation of Hsp70 expression, superoxide dismutase and cytochrome P450 activity in rat brain.

The antistress effect of bacosides of Brahmi (Bacopa monnieri, BBM), dissolved in distilled water, was -studied in adult male Sprague Dawley rats by administering oral doses of 20 and 40 mg/kg for 7 consecutive days. In half of the animals treated with 20 or 40 mg/kg of BBM, stress was given 2 h after the last dose. Stress was also administered to the animals treated with distilled water alone. BBM, at both doses, did not induce a significant change in the expression of Hsp70 in any brain region studied while stress alone produced a significant increase in the Hsp70 expression in all the brain regions. A significant decrease in the activity of superoxide dismutase (SOD) was evident in the hippocampus with the lower dose of BBM and in animals given stress alone, while an increase in the activity of SOD was observed in the brain regions with the higher dose of BBM. An increase in the activity of cytochrome P450 (P450) dependent 7-pentoxyresorufin-o-dealkylase (PROD) and 7-ethoxyresorufin-o-deethylase (EROD) was observed in all the brain regions after exposure to stress alone and with both doses of BBM although the magnitude of induction of P450 expression was less with a higher dose of BBM. Interestingly, stress when given to the animals pretreated with BBM for 7 days resulted in a decrease in Hsp70 expression in all the brain regions with a significant decrease occurring only in the hippocampus. Likewise the activity of SOD was found to be further reduced in all the brain regions in the animals treated with the lower dose of BBM followed by stress. However, when stress was given to the animals pretreated with the higher dose of BBM, a significant increase in the enzyme activity was observed in the cerebral cortex and in the rest of the brain while the activity of SOD was reduced to a much greater extent in the cerebellum and in the hippocampus. Likewise, the activity of P450 enzymes was found to be restored to almost control levels in the animals given stress and pretreated with the higher dose of BBM, while a lesser degree of induction, compared with animals treated with BBM or stress alone, was observed in the animals pretreated with the lower dose of BBM and given stress. The data indicate that BBM has potential to modulate the activities of Hsp70, P450 and SOD thereby possibly allowing the brain to be prepared to act under adverse conditions such as stress.

Administration, Oral↗
PubMed2002

Changes in intraocular pressure following diagnostic mydriasis with cyclopentolate 1%.

PURPOSE: To assess the effect of diagnostic mydriasis with 1% cyclopentolate on the intraocular pressure (IOP) of patients attending glaucoma, medical retina and cataract clinics. METHODS: Levels of agreement for IOP assessment were determined and 95% of repeated readings found to be within +/-2 mmHg. The IOP of 83 cataract, 87 medical retinal and 100 glaucoma patients was measured with Goldmann applanation tonometry before and 45 min after dilatation with 1% cyclopentolate. Those showing a substantial (>10 mmHg) increase in IOP underwent gonioscopy to determine if their angles remained open and were medically treated to lower their IOP. RESULTS: An approximately normal distribution of change in IOP following dilatation was seen in all three groups (mean change 0.4 mmHg (95% CI 0.1-0.8)). The proportion of patients with a rise of 5 mmHg or more in the right eye was 7% (95% CI 4-10%). Logistic regression using all right eyes, looking at age, sex, diagnosis, ethnicity, ocular medication, iris colour and lens status (phakic/pseudophakic/aphakic) as risk factors for a rise of IOP of 5 mmHg or more did not reveal any significant contribution. Correlation between results obtained for right and left eyes in the glaucoma group was lower (0.43) than for the other groups (0.66 and 0.72), but the extent to which the direction of change in one eye predicted that in the other was shown to be high. Two glaucoma patients with open angles developed a clinically important (>10 mmHg) sustained rise in IOP requiring treatment. CONCLUSIONS: Individual variability in the effects of cyclopentolate on aqueous dynamics may account for the approximately normal distribution of IOP seen following dilatation in all three groups. This variation was in excess of that due to observation error alone. It is recommended that the IOP be rechecked after dilation in glaucoma patients with significantly damaged optic nerve heads. In medical retina and cataract patients, sustained clinically important rises in intraocular pressure following dilation seem rarer.

Adult↗
PubMed2002

Naively changing HAART.

BACKGROUND: Few UK studies have systematically investigated which antiretroviral therapy (ART) combinations HIV-infected people are commenced on, when they start and reasons for stopping or changing their regimens. OBJECTIVE: To describe when HIV-infected ART-naive patients started first-, second- or third-line triple ART, classes of drugs prescribed and whether stopping ART was associated with virological, immunological or clinical indicators of treatment failure. DESIGN: A multicentre prospective open cohort study, employing the National Prospective Monitoring System on the use, cost and outcome of HIV service provision in UK hospitals-HIV Health-economics Collaboration (NPMS-HHC). SETTING: Five hundred and eighty-five ART-naive patients seen in one London and two non-London HIV clinics between 1 January 1998 and 31 December 1999. RESULTS: Of 4,044 HIV-infected individuals seen, 585 (15%) were ART naive. Median time interval (interquartile range, IQR) between HIV diagnosis and starting triple ART was 800 (63-2,094) days. Median CD4 count when first diagnosed with HIV infection was 278 (IQR 127-481) cells/ micro L which dropped to 190 (IQR 86-297) cells/ micro L when starting triple ART. Of these 585 patients, 162 started second-line and 46 third-line ART during the study period. Of those patients who stopped ART, 51% did not have evidence of virological, immunological or clinical indicators of therapy failure. CONCLUSIONS: Reasons for the delay between diagnosis of HIV infection and starting ART are varied. The large proportion of individuals who stopped ART for reasons other than virological, immunological or clinical indicators of therapy failure, are most likely due to drug-associated toxicity. Both of these findings need to be elucidated in greater detail through prospective studies.

Adult↗
PubMed2001

Cytochrome P450 1A1 (CYP1A1) in blood lymphocytes evidence for catalytic activity and mRNA expression.

Studies initiated to characterise the catalytic activity and expression of CYP1A1 in rat blood lymphocytes revealed significant activity of 7-ethoxyresorufin-O-deethylase (EROD) in rat blood lymphocytes. Pretreatment with 3-methylcholanthrene (MC) and beta-naphthoflavone (NF) resulted in significant induction in the activity of lymphocyte EROD suggesting that like the liver enzyme, EROD activity in lymphocytes is inducible and is mediated by the MC inducible isoenzymes of P450. The increase in the activity of EROD was associated with a significant increase in the apparent Vmax and affinity of the substrate towards EROD. That this increase in the activity of EROD could be primarily due to the increase in the expression of CYP1A1 isoenzymes was demonstrated by RT-PCR and western immunoblotting studies indicating an increase in the expression of CYP1A1 in blood lymphocytes after MC pretreatment. Significant inhibition in the EROD activity of MC induced lymphocyte by anti-CYP1A1/1A2 and alpha-naphthoflavone further provided evidence that the CYP1A1/1A2 isoenzymes are involved in the activity of EROD in blood lymphocytes. The data indicating similarities in the regulation of CYP1A1 in blood lymphocytes with the liver isoenzyme suggests that factors which may affect expression of CYP1A1 in liver may also affect expression in blood lymphocytes and that blood lymphocytes could be used as a surrogates for studying hepatic expression of the xenobiotic metabolising enzymes.

Animals↗
PubMed2001

Induction of rat brain cytochrome P450s (P450s) by deltamethrin: regional specificity and correlation with neurobehavioral toxicity.

Oral administration of 5 mg/kg body weight of deltamethrin, an alpha-cyano type II pyrethroid insecticide once a day for 1, 7, 15 and 21 consecutive days to young Druckerey rats (6- 8 weeks old) produced a time dependent increase in the activity of cytochrome P450 (P450) dependent 7-ethoxyresorufin-O-deethylase (EROD) and 7-pentoxyresorufin-O-dealkylase (PROD) in rat brain microsomes. A significant induction was observed on prolonged exposure of deltamethrin for 15 or 21 days. The induction in the activity of cerebral P450 enzymes was associated with the time dependent increase in the spontaneous locomotor activity indicating accumulation of deltamethrin or its metabolites in brain with the increase in the duration of exposure. Administration of deltamethrin (5 mg/kg) for 21 days produced region specific changes in the dealkylation of ethoxyresorufin and pentoxyresorufin in rat brain with significant induction occurring in the activity of P450 1A1/2 dependent EROD in cerebellum, hippocampus, hypothalamus and medulla-pons and that of P450 2B1/2 mediated PROD in hippocampus, hypothalamus, corpus striatum and mid brain. The data suggests that the differences in the induction of individual P450 isoenzymes in diverse brain regions could play a role in regulating the response of brain to pyrethroid insecticides by modulating their concentration per se or their active metabolites at the target site(s).

Journal Article↗
PubMed2001

Frequency-doubled Nd:YAG laser for the treatment of exudative diabetic maculopathy.

PURPOSE: To determine the clinical efficacy of frequency-doubled Nd:YAG (FD YAG) laser for the treatment of diabetic clinically significant macular oedema (CSMO). METHODS: A prospective pilot study was carried out on 55 eyes with CSMO. FD YAG laser exposures were applied in a focal or grid pattern. The results were evaluated by Snellen visual acuity, slit-lamp biomicroscopy, colour photography and fundus fluorescein angiography. RESULTS: At mean review of 5.3 months, macular oedema had resolved either completely or partly in 44 (80%) eyes, was unchanged in 10 (18%) eyes and progressed in 1 (2%) eye. Visual acuity improved in 11 (20%), stabilised in 40 (73%) and deteriorated in 4 (7%) eyes. CONCLUSION: FD YAG laser therapy is effective in the treatment of CSMO. It combines the ergonomic advantages of a solid-state laser with the benefits of its wavelength. A comparison between the clinical results of FD YAG and other lasers used in the treatment of CSMO is, however, required.

Adult↗
PubMed2000

An alternative mantle irradiation technique using 3D CT- based treatment planning for female patients with Hodgkin's disease.

PURPOSE: For female patients, radiotherapy treatment for Hodgkin's disease invariably results in the irradiation of breast tissue that may lead to radiation induced secondary cancers. The risk for secondary breast cancer is correlated with dose. We have developed a technique in an attempt to increase breast sparing during mantle field irradiation for female patients. MATERIAL AND METHODS: To minimize the irradiated breast volume, a virtual simulation technique making use of a Styrofoam breast immobilization board has been developed whereby the patient lies prone with the breasts positioned in grooves within the board. The breast position is adjusted using Styrofoam wedges, and breast placement is verified using an AP CT-pilot view. A CT scan of the neck and thoracic regions is taken, and the lymph nodes, breast volume and critical structures are outlined. Virtual simulation of the mantle fields (typically AP/PA isocentric beams) is performed, and beam blocks are drawn on the digitally reconstructed radiographs (DRR) generated by the virtual simulation package. The shielding is designed to allow adequate margins around the lymph nodes while maximizing shielding of the lung and breast tissues. The para-aortic fields are also easily determined through virtual simulation, where multi-planar reconstructions (MPR) and 3D renderings of the patient's CT data are used to determine the field limits and beam gaps. In addition to allowing for the geometric optimization of the positioning of the breasts under the lung shields, the virtual simulation technique provides the necessary information for a 3D dosimetric analysis, including dose-volume histograms (DVHs) of the irradiated breast volume. RESULTS: The 3D breast sparing technique was qualitatively and quantitatively compared to non-CT-based techniques and other 3D techniques currently available to assess the protection of the breasts. In a preliminary analysis, virtual simulation images (DRRs, 3D rendering and multi-planar reconstruction) demonstrated the advantage of using the breast sparing technique. A further analysis of DVHs showed a reduction of at least 50% in the volume of breast tissue irradiated when using the breast positioning board and virtual simulation as compared to the conventional simulation techniques where a breast immobilization board was not used. CONCLUSIONS: The use of a breast immobilization board and of a virtual simulation technique is recommended for the planning and treatment of female patients with Hodgkin's disease. DVH analysis has shown that this leads to a decrease in the volume of breast irradiated. It is hoped that this approach will reduce the risk of secondary breast malignancies in female patients with Hodgkin's disease.

Breast↗
PubMed1999

Cytochrome P450 (P450) isoenzyme specific dealkylation of alkoxyresorufins in rat brain microsomes.

Characterization of xenobiotic metabolizing cytochrome P450s (P450s) was carried out in rat brain microsomes using the specific substrates, 7-pentoxy- and 7-ethoxyresorufin (PR and ER), metabolized in the liver by P450 2B1/2B2 and 1A1/1A2 respectively and 7-benzyloxyresorufin (BR), a substrate for both the isoenzymes. Brain microsomes catalysed the O-dealkylation of PR, BR and ER in the presence of NADPH. The ability to dealkylate alkoxyresorufins varied in different regions of the brain. Microsomes from the olfactory lobes exhibited maximum pentoxyresorufin-O-dealkylase (PROD), benzyloxyresorufin-O-dealkylase (BROD) and ethoxyresorufin-O-dealkylase (EROD) activities. The dealkylation was found to be inducer selective. While pretreatment with phenobarbital (PB; 80 mg/kg; i.p. x 5 days) resulted in significant induction in PROD (3-4 fold) and BROD (4-5 fold) activities, 3-methylcholanthrene (MC; 30 mg/kg; i.p. x 5 days) had no effect on the activity of PROD and only a slight effect on that of BROD (1.4 fold). MC pretreatment significantly induced the activity of EROD (3 fold) while PB had no effect on it. Kinetic studies have shown that this increase in the activities following pretreatment with P450 inducers was associated with a significant increase in the velocity of the reaction (Vmax) of O-dealkylation. In vitro studies using organic inhibitors and antibodies have further provided evidence that the O-dealkylation of alkoxyresorufins is isoenzyme specific. While in vitro addition of alpha-naphthoflavone (ANF), an inhibitor of P450 1A1/1A2 catalysed reactions and antibody for hepatic P450 1A1/1A2 isoenzymes produced a concentration-dependent inhibition of EROD activity, metyrapone, an inhibitor of P450 2B1/2B2 and antibody for hepatic P450 2B1/2B2 significantly inhibited the activity of PROD and BROD in vitro. The data suggest that, as in the case of liver, dealkylation of alkoxyresorufins can be used as a biochemical tool to characterise the xenobiotic metabolising P450s and substrate selectivity of P450 isoenzymes in rat brain microsomes.

Alkylation↗
PubMed1998

Evidence for O-dealkylation of 7-pentoxyresorufin by cytochrome P450 2B1/2B2 isoenzymes in brain.

O-dealkylation of 7-pentoxyresorufin (PR) was studied in rat brain to characterise the functional activity specific for cytochrome P450 2B1/2B2 isoenzymes in brain microsomes. Brain microsomes catalyzed the O-dealkylation of PR in the presence of NADPH. Pretreatment with phenobarbital (PB; 80 mg/kg body wt, i.p. x 5 days) resulted in 3-4 fold induction of pentoxyresorufin-O-dealkylase (PROD) activity while 3-methylcholanthrene (MC; 30 mg/kg body wt, i.p. x 5 days) did not produce any significant increase in enzyme activity. Kinetic studies revealed that the rate of velocity (Vmax) for the O-dealkylation of PR was significantly increased to 2.9 times higher in brain microsomes isolated from PB pretreated rats. In vitro studies using metyrapone, an inhibitor of P450 2B1/2B2 catalyzed reactions and antibody for hepatic PB inducible P450s (P450 2B1/2B2) significantly inhibited the activity of PROD in cerebral microsomes prepared from PB pretreated animals. These studies suggest that PB inducible isoenzymes of P450, i.e. P450 2B1/2B2 specifically catalyze the O-dealkylation of PR in brain microsomes.

Animals↗
PubMed1998

Clinicopathological study of seven cases of spinal cord teratoma: a possible germ cell origin.

AIMS: To establish the clinical and pathological aspects of teratoma affecting the spinal cord. METHOD AND RESULTS: We reviewed our neurosurgical records for the last 15 years and found seven cases of teratoma of the spinal cord. The cases were reviewed clinically, radiologically and pathologically using immunohistochemical markers to identify various tissue components. We found that spinal cord teratoma is an extremely rare tumour of spinal cord affecting patients aged 23-47 years and of approximately equal male to female distribution. The terminal portions of spinal cord and intradural location of the tumour are common. Three cases were associated with vertebral anomaly. Most tumours showed benign (mature) components derived from more than one germ cell layer; one showed malignant adenocarcinomatous component. All cases were treated by surgical resection and two recurred at 6 and 10 year intervals without malignant transformation. CONCLUSION: Spinal cord teratoma is a rare, mainly benign tumour, which could be associated with vertebral anomaly. The pathogenesis of this tumour is controversial, possibly due to germinal cell aberration.

Adenocarcinoma↗
PubMed1995

Testicular toxicity of Di(2-ethylhexyl)phthalate in developing rats.

To understand the factors involved in the enhanced testicular toxicity of di(2-ethylhexyl)phthalate (DEHP) in developing animals, po doses of 50, 100, 250 or 500 mg DEHP/kg were administered to 25-d-old albino rats for 30 consecutive days. Activities of testicular and hepatic cytochrome P-450 enzymes were determined. A dose-dependent increase in the activities of lactate dehydrogenase and gamma-glutamyl transpeptidase and a decrease in sorbitol dehydrogenase was observed in the testes. The activity of beta-glucuronidase increased at dosages of 250 and 500 mg/kg, while acid phosphatase decreased. Testes had marked destructive changes in the advanced germ cell layers at dosages of 250 and 500 mg/kg, which supports biochemical studies indicating that DEHP interacts with the maturation process of the testes. The dose-dependent decrease in hepatic cytochrome P-450 levels and the activities of ethylmorphine N-demethylase and aniline hydroxylase suggest that impaired metabolism of DEHP could lead to higher amounts of the diester or its metabolites reaching the testes; this may result in enhanced vulnerability of the testes to DEHP in developing animals.

Aging↗
PubMed1994

The induction of five rat hepatic P450 cytochromes by phenobarbital and similarly acting compounds is regulated by a sexually dimorphic, dietary-dependent endocrine factor that is highly strain specific.

The phenobarbital (PB)-mediated expression of five forms of cytochrome P450 (CYP2A1, CYP2B1, CYP2B2, CYP2C6, and CYP3A1) and epoxide hydrolase has been examined in male and female rats from three inbred strains [Fischer (F344), Wistar Furth (WF), and Wistar Kyoto (WK)]. Evidence is presented that the regulation of induction of each protein involves a very similar endocrine control process. Each induction shows the same marked strain differences that are observable to a much greater extent in females than in males. The differences are largely removed by hypophysectomy and are each greatly enhanced by a shift in diet (standard [Teklad (W) 8604] to defined [Teklad AIN-76A]). The induction of each gene in female rats, as measured by specific immunoblots, follows the same strain selectivity (F344 >> WK > WF). These differences were similarly demonstrated in isoform-specific metabolism and comparable variations in the levels of the specific P450 mRNA suggest that these differences reflect alterations in gene transcription. For CYP3A1, CYP2B1, and CYP2B2, the differences between the F344 and WF strains approach 10-fold when using the defined diet, while the differences decreased approximately 3-fold with the standard chow, in parallel with much more effective induction of total P450. The same trend was also observed for the induction of CYP2A1, CYP2C6, and epoxide hydrolase, but the differences were less because of higher constitutive levels which were insensitive to these effects and smaller induction factors. These strain differences were not observed for CYP1A2, which is unresponsive to PB. Similar sex- and strain-selectivity for each P450 gene occurs for D-limonene, a structurally and chemically dissimilar PB-type inducer. Each of these measurements indicates a suppression of expression in female WF rats relative to a set of similar levels in male WF rats and F344 rats of both sexes. Hypophysectomy relieves the suppression through selective stimulation of induced levels in female WF rats. Many of the same differences between the F344 and WF strains can be observed in the very low basal expression of these PB-inducible genes. Thus, we have identified a gender-selective, pituitary-mediated polymorphism that probably affects basal regulatory factors.

Animals↗
PubMed1993

Studies on the interaction of furan with hepatic cytochrome P-450.

In vitro incubation of rat liver microsomes with [14C]-furan in the presence of NADPH resulted in the covalent incorporation of furan-derived radioactivity in microsomal protein. Compared to microsomes from untreated rats a two- to threefold increase in binding was observed with microsomes from phenobarbital-treated rats and a four- to five-fold increase was observed with microsomes from rats pretreated with imidazole or pyrazole. Covalent binding was reduced with microsomes from rats pretreated with beta-naphthoflavone. Chemicals containing an amine group (semi-carbazide), those in which the amine group is blocked but have a free thiol group (N-acetylcysteine), and those which have both an amine and a thiol group (glutathione) effectively blocked binding of [14C]-furan to microsomal protein. A decrease in cytochrome P-450 (P-450) content and decreases in the activities of P-450-dependent aniline hydroxylase, 7-ethoxycoumarin-O-deethylase (ECD), and 7-ethoxyresorufin-O-deethylase (ERD) was observed 24 hours after a single oral administration of 8 or 25 mg/kg of furan, suggesting that the reactive intermediate formed during P-450 catalyzed metabolism could be binding with nucleophilic groups within the P-450. In vitro studies indicated a significant decrease in the activity of aniline hydroxylase in pyrazole microsomes and ECD in phenobarbital microsomes without any significant change in the CO-binding spectrum of P-450 or in the total microsomal heme content, suggesting that furan inhibits the P-450s induced by PB and pyrazole.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗