364 results on '"Parkinson, Andrew"'
Search Results
352. The development and evaluation of radiological decontamination procedures for documents, document inks, and latent fingermarks on porous surfaces.
- Author
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Parkinson A, Colella M, and Evans T
- Subjects
- Chromatography, Thin Layer, Humans, Indicators and Reagents, Ink, Microspectrophotometry, Ninhydrin, Porosity, Surface Properties, Decontamination methods, Dermatoglyphics
- Abstract
Criminal acts such as an attack utilizing a radiological dispersal device (RDD or dirty bomb), the manufacture of such a device, or the illicit trafficking of radioactive materials would warrant a criminal investigation. This could involve the collection, transportation, and analysis of radiologically contaminated trace evidence. But are law enforcement agencies and forensic scientists capable of dealing with this? This research investigates the decontamination efficacy of two decontamination techniques (chemical and physical) designed for the removal of radiological material from documents of forensic importance. The impact that these procedures have on the development of latent fingermarks and the forensic analysis of the inks on these documents is also studied. It was found that slight changes in the color and chemical composition of a variety of document inks and a destruction of fingermark ridges occurred after chemical decontamination. Physical decontamination had no impact on these parameters.
- Published
- 2010
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353. System-dependent outcomes during the evaluation of drug candidates as inhibitors of cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) enzymes: human hepatocytes versus liver microsomes versus recombinant enzymes.
- Author
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Parkinson A, Kazmi F, Buckley DB, Yerino P, Ogilvie BW, and Paris BL
- Subjects
- Azetidines pharmacology, Bupropion pharmacology, Drug Interactions, Ezetimibe, Gemfibrozil pharmacology, Humans, Cytochrome P-450 Enzyme Inhibitors, Drug Evaluation, Preclinical methods, Enzyme Inhibitors pharmacology, Glucuronosyltransferase antagonists & inhibitors, Hepatocytes drug effects, Microsomes, Liver drug effects, Recombinant Proteins drug effects
- Abstract
The ability of a drug to cause clinically significant drug-drug interactions due to direct or metabolism-dependent inhibition of cytochrome P450 (CYP) can generally be predicted from in vitro studies with human liver microsomes (HLM) or recombinant CYP enzymes, as recommended by the FDA and other regulatory agencies. This review highlights some examples of system-dependent inhibition of CYP and uridine diphosphate glucuronosyltransferase (UGT) enzymes. In the case of CYP enzymes, examples are presented where in vitro studies with HLM under-predict or over-predict the degree of inhibition observed in the clinic and where the correct prediction comes from studies with human hepatocytes. Studies with HLM under-predict the ability of gemfibrozil and bupropion to cause clinically significant inhibition of CYP2C8 and CYP2D6, respectively, and over-predict the ability of ezetimibe to cause clinically significant inhibition of CYP3A4. Gemfibrozil and bupropion represent examples of glucuronidation-dependent and reduction-dependent activation to metabolites that inhibit CYP2C8 and CYP2D6, respectively, whereas ezetimibe represents an example of glucuronidation-dependent protection against metabolism-dependent inhibition of CYP3A4. This article illustrates why, when drug candidates are extensively metabolized by non-CYP enzymes, it would be prudent to use human hepatocytes in addition to HLM or recombinant enzymes to evaluate their ability to inhibit CYP enzymes.
- Published
- 2010
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354. Construction of triple-transfected cells [organic anion-transporting polypeptide (OATP) 1B1/multidrug resistance-associated protein (MRP) 2/MRP3 and OATP1B1/MRP2/MRP4] for analysis of the sinusoidal function of MRP3 and MRP4.
- Author
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Hirouchi M, Kusuhara H, Onuki R, Ogilvie BW, Parkinson A, and Sugiyama Y
- Subjects
- ATP-Binding Cassette Transporters metabolism, Animals, Cells, Cultured, Hepatocytes, Hymecromone pharmacology, Male, Mice, Mice, Knockout, Multidrug Resistance-Associated Protein 2, Multidrug Resistance-Associated Proteins genetics, Organic Anion Transporters physiology, Organic Anion Transporters, Sodium-Independent physiology, Swine, Multidrug Resistance-Associated Proteins physiology, Organic Anion Transporters genetics, Organic Anion Transporters, Sodium-Independent genetics, Transfection
- Abstract
Multidrug resistance-associated protein (MRP) 3/ABCC3 and MRP4/ABCC4 are ATP-binding cassette (ABC) transporters expressed in the sinusoidal membrane of hepatocytes. The purpose of the present study was to establish organic anion-transporting polypeptide (OATP) 1B1/MRP2/MRP3 and OATP1B1/MRP2/MRP4 triple transfectants as in vitro model of the hepatobiliary transport of anionic drugs. To find in vivo relevant Mrp3 probes, wild-type and Mrp3(-/-) mice were given gemfibrozil, 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridymethyl)benzothiazole (E3040), troglitazone, bisphenol A, and 4-methylumbelliferone orally. Plasma concentrations of the glucuronide conjugates were significantly lower in Mrp3(-/-) mice than in wild-type mice. The systemic exposure of gemfibrozil, E3040, and troglitazone were similar in wild-type and Mrp3(-/-) mice. 4-Methylumbelliferone and bisphenol A were undetectable in the plasma. In MRP3-expressing membrane vesicles, ATP-dependent uptakes of the glucuronide conjugates of estradiol, gemfibrozil, E3040, and troglitazone were markedly greater than those in controls, whereas MRP4-expressing membrane vesicles exhibited significant ATP-dependent uptake of gemfibrozil glucuronide and estradiol glucuronide. MRP3 or MRP4 was expressed in the OATP1B1/MRP2 double transfectants using adenovirus. The expression levels of OATP1B1 and MRP2 proteins were maintained both in the OATP1B1/MRP2/MRP3 and OATP1B1/MRP2/MRP4 triple transfectants, whereas MRP3 and MRP4 were localized in the basal membrane. Significant reductions in the basal-to-apical flux of the glucuronide conjugates of estradiol, gemfibrozil, E3040, and troglitazone were observed in the OATP1B1/MRP2/MRP3 triple transfectants compared with those in the double transfectants, whereas significant reduction was observed only for gemfibrozil glucuronide and estradiol glucuronide in the OATP1B1/MRP2/MRP4 triple transfectants. These results suggest that MRP3- or MRP4-triple transfectants provide a simple and useful in vitro system for evaluating their importance in the hepatobiliary transport of drugs.
- Published
- 2009
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355. In vitro inhibition and induction of human liver cytochrome p450 enzymes by milnacipran.
- Author
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Paris BL, Ogilvie BW, Scheinkoenig JA, Ndikum-Moffor F, Gibson R, and Parkinson A
- Subjects
- Aged, Anti-Ulcer Agents pharmacology, Antitubercular Agents pharmacology, Cytochrome P-450 CYP1A2 metabolism, Cytochrome P-450 CYP2D6 metabolism, Cytochrome P-450 CYP3A metabolism, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System metabolism, Drug Interactions, Enzyme Induction drug effects, Hepatocytes enzymology, Humans, Hypoglycemic Agents pharmacology, Male, Microsomes, Liver enzymology, Midazolam pharmacology, Middle Aged, Milnacipran, Omeprazole pharmacology, Testosterone pharmacology, Cyclopropanes pharmacology, Cytochrome P-450 Enzyme System drug effects, Hepatocytes drug effects, Microsomes, Liver drug effects, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
Milnacipran (Savella) inhibits both norepinephrine and serotonin reuptake and is distinguished by a nearly 3-fold greater potency in inhibiting norepinephrine reuptake in vitro compared with serotonin. We evaluated the ability of milnacipran to inhibit and induce human cytochrome P450 enzymes in vitro. In human liver microsomes, milnacipran did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 (IC(50) >or= 100 microM); whereas, a comparator with dual reuptake properties [duloxetine (Cymbalta)] inhibited CYP2D6 (IC(50) = 7 microM) and CYP2B6 (IC(50) = 15 microM) with a relatively high potency. Milnacipran inhibited CYP3A4/5 in a substrate-dependent manner (i.e., midazolam 1'-hydroxylation IC(50) approximately 30 microM; testosterone 6beta-hydroxylation IC(50) approximately 100 microM); whereas, duloxetine inhibited both CYP3A4/5 activities with equal potency (IC(50) = 37 and 38 microM, respectively). Milnacipran produced no time-dependent inhibition (<10%) of P450 activity, whereas duloxetine produced time-dependent inhibition of CYP1A2, 2B6, 2C19, and 3A4/5. To evaluate P450 induction, freshly isolated human hepatocytes (n = 3) were cultured and treated once daily for 3 days with milnacipran (3, 10, and 30 microM), after which microsomal P450 activities were measured. Whereas positive controls (omeprazole, phenobarbital, and rifampin) caused anticipated P450 induction, milnacipran had minimal effect on CYP1A2, 2C8, 2C9, or 2C19 activity. The highest concentration of milnacipran (30 microM; >10 times plasma C(max)) produced 2.6- and 2.2-fold increases in CYP2B6 and CYP3A4/5 activity (making it 26 and 34% as effective as phenobarbital and rifampin, respectively). Given these results, milnacipran is not expected to cause clinically significant P450 inhibition or induction.
- Published
- 2009
- Full Text
- View/download PDF
356. An in vitro evaluation of the victim and perpetrator potential of the anticancer agent laromustine (VNP40101M), based on reaction phenotyping and inhibition and induction of cytochrome P450 enzymes.
- Author
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Nassar AE, King I, Paris BL, Haupt L, Ndikum-Moffor F, Campbell R, Usuki E, Skibbe J, Brobst D, Ogilvie BW, and Parkinson A
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Area Under Curve, Dogs, Drug Interactions, Enzyme Induction drug effects, Haplorhini, Humans, Hydrazines pharmacokinetics, Hydroxylation, In Vitro Techniques, Isoenzymes antagonists & inhibitors, Isoenzymes biosynthesis, Microsomes, Liver enzymology, Microsomes, Liver metabolism, NADP metabolism, Phenotype, Rats, Sulfonamides pharmacokinetics, Antineoplastic Agents pharmacology, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System biosynthesis, Hydrazines pharmacology, Sulfonamides pharmacology
- Abstract
Laromustine (VNP40101M, also known as Cloretazine) is a novel sulfonylhydrazine alkylating (anticancer) agent. Laromustine generates two types of reactive intermediates: 90CE and methylisocyanate. When incubated with rat, dog, monkey, and human liver microsomes, [(14)C]laromustine was converted to 90CE (C-8) and seven other radioactive components (C-1-C-7). There was little difference in the metabolite profile among the species examined, in part because the formation of most components (C-1-C-6 and 90CE) did not require NADPH but involved decomposition and/or hydrolysis. The exception was C-7, a hydroxylated metabolite, largely formed by CYP2B6 and CYP3A4/5. Laromustine caused direct inhibition of CYP2B6 and CYP3A4/5 (the two enzymes involved in C-7 formation) as well as of CYP2C19. K(i) values were 125 microM for CYP2B6, 297 muM for CYP3A4/5, and 349 microM for CYP2C19 and were greater than the average clinical plasma C(max) of laromustine (25 microM). There was evidence of time-dependent inhibition of CYP1A2, CYP2B6, and CYP3A4/5. Treatment of primary cultures of human hepatocytes with up to 100 microM laromustine did not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5, but the highest concentration of laromustine decreased the activity and levels of immunoreactive CYP3A4. The results of this study suggest the laromustine has 1) negligible victim potential with respect to metabolism by cytochrome P450 enzymes, 2) negligible enzyme-inducing potential, and 3) the potential in some cases to cause inhibition of CYP2B6, CYP3A4, and possibly CYP2C19 during and shortly after the duration of intravenous administration of this anticancer drug, but the clinical effects of such interactions are likely to be insignificant.
- Published
- 2009
- Full Text
- View/download PDF
357. The recovery of latent fingermarks from evidence exposed to ionizing radiation*.
- Author
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Colella M, Parkinson A, Evans T, Lennard C, and Roux C
- Subjects
- Aluminum, Aza Compounds, Cesium Radioisotopes, Cobalt Radioisotopes, Cyanoacrylates, Dose-Response Relationship, Radiation, Fluorescent Dyes, Glass, Humans, Indans, Indicators and Reagents, Iridium Radioisotopes, Ninhydrin, Paper, Polyethylenes, Polystyrenes, Rhodamines, Surface Properties, Dermatoglyphics, Radiation, Ionizing
- Abstract
Continual reports of illicit trafficking incidents involving radioactive materials have prompted authorities to consider the likelihood of forensic evidence being exposed to radiation. In this study, we investigated the ability to recover latent fingermark evidence from a variety of substrates that were exposed to ionizing radiation. Fingermarks deposited on common surfaces, including aluminum, glass, office paper, and plastic, were exposed to doses ranging from 1 to 1000 kGy, in an effort to simulate realistic situations where evidence is exposed to significant doses of radiation from sources used in a criminal act. The fingermarks were processed using routine fingermark detection techniques. With the exception of glass and aluminum substrates, radiolysis had a considerable effect on the quality of the developed fingermarks. The damage to ridge characteristics can, in part, be attributed to chemical interactions between the substrate and the components of the fingermark secretions that react with the detection reagents.
- Published
- 2009
- Full Text
- View/download PDF
358. Expression of constitutive androstane receptor, hepatic nuclear factor 4 alpha, and P450 oxidoreductase genes determines interindividual variability in basal expression and activity of a broad scope of xenobiotic metabolism genes in the human liver.
- Author
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Wortham M, Czerwinski M, He L, Parkinson A, and Wan YJ
- Subjects
- Adolescent, Adult, Aged, Biomarkers, Child, Child, Preschool, Constitutive Androstane Receptor, Cytochrome P-450 Enzyme System genetics, Female, Hepatocyte Nuclear Factor 4 genetics, Humans, Infant, Infant, Newborn, Isoenzymes biosynthesis, Isoenzymes genetics, Liver growth & development, Male, Microsomes, Liver drug effects, Microsomes, Liver enzymology, Middle Aged, RNA, Messenger biosynthesis, RNA, Messenger genetics, Receptors, Cytoplasmic and Nuclear genetics, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, Transcription Factors genetics, Cytochrome P-450 Enzyme System biosynthesis, Hepatocyte Nuclear Factor 4 biosynthesis, Liver metabolism, Receptors, Cytoplasmic and Nuclear biosynthesis, Transcription Factors biosynthesis, Xenobiotics metabolism
- Abstract
Identification of genetic variation predictive of clearance rate of a wide variety of prescription drugs could lead to cost-effective personalized medicine. Here we identify regulatory genes whose variable expression level among individuals may have widespread effects upon clearance rate of a variety of drugs. Twenty liver samples with variable CYP3A activity were profiled for expression level and activity of xenobiotic metabolism genes as well as genes involved in the regulation thereof. Regulatory genes whose expression level accounted for the highest degree of collinearity among expression levels of xenobiotic metabolism genes were identified as possible master regulators of drug clearance rate. Significant linear correlations (p < 0.05) were identified among mRNA levels of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, MRP2, OATP2, P450 oxidoreductase (POR), and UDP-glucuronosyltranferase 1A1, suggesting that these xenobiotic metabolism genes are coregulated at the transcriptional level. Using partial regression analysis, constitutive androstane receptor (CAR) and hepatic nuclear factor 4 alpha (HNF4 alpha) were identified as the nuclear receptors whose expression levels are most strongly associated with expression of coregulated xenobiotic metabolism genes. POR expression level, which is also associated with CAR and HNF4 alpha expression level, was found to be strongly associated with the activity of many cytochromes P450. Thus, interindividual variation in the expression level of CAR, HNF4 alpha, and POR probably determines variation in expression and activity of a broad scope of xenobiotic metabolism genes and, accordingly, clearance rate of a variety of xenobiotics. Identification of polymorphisms in these candidate master regulator genes that account for their variable expression among individuals may yield readily detectable biomarkers that could serve as predictors of xenobiotic clearance rate.
- Published
- 2007
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359. Evaluation of felbamate and other antiepileptic drug toxicity potential based on hepatic protein covalent binding and gene expression.
- Author
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Leone AM, Kao LM, McMillian MK, Nie AY, Parker JB, Kelley MF, Usuki E, Parkinson A, Lord PG, and Johnson MD
- Subjects
- Animals, Cells, Cultured, Epilepsy pathology, Felbamate, Humans, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Protein Binding, Rats, Anticonvulsants toxicity, Epilepsy drug therapy, Gene Expression Regulation drug effects, Liver drug effects, Liver metabolism, Phenylcarbamates toxicity, Propylene Glycols toxicity
- Abstract
Felbamate is an antiepileptic drug that is associated with minimal toxicity in preclinical species such as rat and dog but has an unacceptable incidence of serious idiosyncratic reactions in man. Idiosyncratic reactions account for over half of toxicity-related drug failures in the marketplace, and improving the preclinical detection of idiosyncratic toxicities is thus of paramount importance to the pharmaceutical industry. The formation of reactive metabolites is common among most drugs associated with idiosyncratic drug reactions and may cause deleterious effects through covalent binding and/or oxidative stress. In the present study, felbamate was compared to several other antiepileptic drugs (valproic acid, carbamazepine, phenobarbital, and phenytoin), using covalent binding of radiolabeled drugs and hepatic gene expression responses to evaluate oxidative stress/reactive metabolite potential. Despite causing only very mild effects on covalent binding parameters, felbamate produced robust effects on a previously established oxidative stress/reactive metabolite gene expression signature. The other antiepileptic drugs and acetaminophen are known hepatotoxicants at high doses in the rat, and all increased covalent binding to liver proteins in vivo and/or to liver microsomes from human and rat. With the exception of acetaminophen, valproic acid exhibited the highest covalent binding in vivo, whereas carbamazepine exhibited the highest levels in vitro. Pronounced effects on oxidative stress/reactive metabolite-responsive gene expression were observed after carbamazepine, phenobarbital, and phenytoin administration. Valproic acid had only minor effects on the oxidative stress/reactive metabolite indicator genes. The relative ease of detection of felbamate based on gene expression results in rat liver as having potential oxidative stressor/reactive metabolites indicates that this approach may be useful in screening for potential idiosyncratic toxicity. Together, measurements of gene expression along with covalent binding should improve the safety assessment of candidate drugs.
- Published
- 2007
- Full Text
- View/download PDF
360. CYP4F enzymes are the major enzymes in human liver microsomes that catalyze the O-demethylation of the antiparasitic prodrug DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime].
- Author
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Wang MZ, Saulter JY, Usuki E, Cheung YL, Hall M, Bridges AS, Loewen G, Parkinson OT, Stephens CE, Allen JL, Zeldin DC, Boykin DW, Tidwell RR, Parkinson A, Paine MF, and Hall JE
- Subjects
- Cytochrome P-450 Enzyme Inhibitors, Enzyme Inhibitors metabolism, Humans, In Vitro Techniques, Microsomes, Liver metabolism, Antiparasitic Agents metabolism, Benzamidines metabolism, Cytochrome P-450 Enzyme System metabolism, Prodrugs metabolism
- Abstract
DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime] is biotransformed to the potent antiparasitic diamidine DB75 [2,5-bis(4-amidinophenyl) furan] by sequential oxidative O-demethylation and reductive N-dehydroxylation reactions. Previous work demonstrated that the N-dehydroxylation reactions are catalyzed by cytochrome b5/NADH-cytochrome b5 reductase. Enzymes responsible for catalyzing the DB289 O-demethylation pathway have not been identified. We report an in vitro metabolism study to characterize enzymes in human liver microsomes (HLMs) that catalyze the initial O-demethylation of DB289 (M1 formation). Potent inhibition by 1-aminobenzotriazole confirmed that M1 formation is catalyzed by P450 enzymes. M1 formation by HLMs was NADPH-dependent, with a Km and Vmax of 0.5 microM and 3.8 nmol/min/mg protein, respectively. Initial screening showed that recombinant CYP1A1, CYP1A2, and CYP1B1 were efficient catalysts of M1 formation. However, none of these three enzymes was responsible for M1 formation by HLMs. Further screening showed that recombinant CYP2J2, CYP4F2, and CYP4F3B could also catalyze M1 formation. An antibody against CYP4F2, which inhibited both CYP4F2 and CYP4F3B, inhibited 91% of M1 formation by HLMs. Two inhibitors of P450-mediated arachidonic acid metabolism, HET0016 (N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine) and 17-octadecynoic acid, effectively inhibited M1 formation by HLMs. Inhibition studies with ebastine and antibodies against CYP2J2 suggested that CYP2J2 was not involved in M1 formation by HLMs. Additionally, ketoconazole preferentially inhibited CYP4F2, but not CYP4F3B, and partially inhibited M1 formation by HLMs. We conclude that CYP4F enzymes (e.g., CYP4F2, CYP4F3B) are the major enzymes responsible for M1 formation by HLMs. These findings indicate that, in human liver, members of the CYP4F subfamily biotransform not only endogenous compounds but also xenobiotics.
- Published
- 2006
- Full Text
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361. Anabolic androgenic steroids: a survey of 500 users.
- Author
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Parkinson AB and Evans NA
- Subjects
- Adolescent, Adult, Anabolic Agents adverse effects, Attitude to Health, Female, Humans, Internet, Male, Polypharmacy, Substance-Related Disorders epidemiology, Surveys and Questionnaires, Testosterone Congeners adverse effects, Anabolic Agents administration & dosage, Body Image, Testosterone Congeners administration & dosage
- Abstract
Purpose: The use of anabolic androgenic steroids (AAS) to increase muscle size and strength is widespread. Information regarding self-administered AAS used nonmedically to enhance athletic performance or improve physical appearance is sparse and poorly documented. The purpose of this study is to identify current trends in the drug-taking habits of AAS users., Methods: An anonymous self-administered questionnaire was posted on the message boards of Internet Web sites popular among AAS users., Results: Of the 500 AAS users who participated in the survey, 78.4% (392/500) were noncompetitive bodybuilders and nonathletes; 59.6% (298/500) of the respondents reported using at least 1000 mg of testosterone or its equivalent per week. The majority (99.2%) of AAS users (496/500) self-administer injectable AAS formulations, and up to 13% (65/500) report unsafe injection practices such as reusing needles, sharing needles, and sharing multidose vials. In addition to using AAS, 25% of users admitted to the adjuvant use of growth hormone and insulin for anabolic effect, and 99.2% (496/500) of users reported subjective side effects from AAS use., Conclusions: This survey reveals several trends in the nonmedical use of AAS. Nearly four out of five AAS users are nonathletes who take these drugs for cosmetic reasons. AAS users in this sample are taking larger doses than previously recorded, with more than half of the respondents using a weekly AAS dose in excess of 1000 mg. The majority of steroid users self-administer AAS by intramuscular injection, and approximately 1 in 10 users report hazardous injection techniques. Polypharmacy is practiced by more than 95% of AAS users, with one in four users taking growth hormone and insulin. Nearly 100% of AAS users reported subjective side effects.
- Published
- 2006
- Full Text
- View/download PDF
362. On the mechanism of hepatocarcinogenesis of benzodiazepines: evidence that diazepam and oxazepam are CYP2B inducers in rats, and both CYP2B and CYP4A inducers in mice.
- Author
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Parkinson A, Leonard N, Draper A, and Ogilvie BW
- Subjects
- Animals, Blotting, Western, Body Weight drug effects, Cytochrome P-450 CYP1A1 biosynthesis, Cytochrome P-450 CYP2B1 biosynthesis, Immunohistochemistry, Isoenzymes biosynthesis, Lauric Acids metabolism, Male, Mice, Microsomes, Liver drug effects, Microsomes, Liver enzymology, Nitrophenols metabolism, Organ Size drug effects, Phenobarbital pharmacology, Rats, Rats, Sprague-Dawley, Benzodiazepines toxicity, Carcinogens, Cytochrome P-450 CYP4A biosynthesis, Cytochrome P-450 Enzyme System biosynthesis, Diazepam toxicity, Hypnotics and Sedatives toxicity, Liver Neoplasms chemically induced, Oxazepam toxicity
- Abstract
The aim of this study was to evaluate diazepam and oxazepam as cytochrome P450 inducers at doses previously shown to cause liver tumors in mice but not rats. In rats, diazepam and oxazepam induced CYP2B, and were as effective as phenobarbital despite lacking phenobarbital's tumor-promoting effect in rats. In mice, diazepam and oxazepam induced both CYP2B and CYP4A at dietary doses associated with liver tumor formation. It remains to be determined why diazepam and oxazepam induce CYP4A in mice but not rats and whether this difference accounts for the apparent species difference in the tumor-promoting activity of diazepam and oxazepam.
- Published
- 2006
- Full Text
- View/download PDF
363. The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes.
- Author
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Parkinson A, Mudra DR, Johnson C, Dwyer A, and Carroll KM
- Subjects
- Aging physiology, Alcohol Drinking metabolism, Animals, Cells, Cultured, Cytochrome P-450 Enzyme System biosynthesis, Cytochrome P-450 Enzyme System genetics, Enzyme Induction drug effects, Ethnicity, Female, Humans, Isoenzymes biosynthesis, Isoenzymes genetics, Isoenzymes metabolism, Male, Sex Characteristics, Smoking metabolism, Cytochrome P-450 Enzyme System metabolism, Hepatocytes enzymology, Liver Cirrhosis enzymology, Microsomes, Liver enzymology
- Abstract
We have measured cytochrome P450 (CYP) activity in nearly 150 samples of human liver microsomes and 64 samples of cryopreserved human hepatocytes, and we have performed induction studies in over 90 preparations of cultured human hepatocytes. We have analyzed these data to examine whether the expression of CYP enzyme activity in liver microsomes and isolated hepatocytes or the inducibility of CYP enzymes in cultured hepatocytes is influenced by the gender, age, or ethnicity of the donor (the latter being limited to Caucasians, African Americans, and Hispanics due to a paucity of livers from Asian donors). In human liver microsomes, there were no statistically significant differences (P > 0.05) in CYP activity as a function of age, gender, or ethnicity with one exception. 7-Ethoxyresorufin O-dealkylase (CYP1A2) activity was greater in males than females, which is consistent with clinical observation. Liver microsomal testosterone 6beta-hydroxylase (CYP3A4) activity was slightly greater in females than males, but the difference was not significant. However, in cryopreserved human hepatocytes, the gender difference in CYP3A4 activity (females = twice males) did reach statistical significance, which supports the clinical observation that females metabolize certain CYP3A4 substrates faster than do males. Compared with those from Caucasians and African Americans, liver microsomes from Hispanics had about twice the average activity of CYP2A6, CYP2B6, and CYP2C8 and half the activity of CYP1A2, although this apparent ethnic difference may be a consequence of the relatively low number of Hispanic donors. Primary cultures of hepatocytes were treated with beta-naphthoflavone, an inducer of CYP1A2, phenobarbital or rifampin, both of which induce CYP2B6, CYP2C9, CYP2C19, and CYP3A4, albeit it to different extents. Induction of these CYP enzymes in freshly cultured hepatocytes did not appear to be influenced by the gender or age of the donor. Furthermore, CYP3A4 induction in hepatocytes isolated from cirrhotic liver was comparable to that in normal hepatocytes, which supports the "healthy hepatocyte, sick environment" hypothesis of liver cirrhosis. This review summarizes these findings and discusses their implications for the use of human liver microsomes and hepatocytes for in vitro studies of drug metabolism and enzyme induction, which play a key role in drug development.
- Published
- 2004
- Full Text
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364. Analysis of CYP mRNA expression by branched DNA technology.
- Author
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Czerwinski M, Opdam P, Madan A, Carroll K, Mudra DR, Gan LL, Luo G, and Parkinson A
- Subjects
- DNA Probes, Gene Expression Regulation, Glucuronosyltransferase genetics, Hepatocytes enzymology, Humans, RNA, Messenger genetics, Sulfotransferases genetics, Branched DNA Signal Amplification Assay methods, Cytochrome P-450 Enzyme System genetics, RNA, Messenger metabolism
- Published
- 2002
- Full Text
- View/download PDF
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