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A Boobis

Publications and source records attributed to A Boobis.

13 recordsLinked to original sources
PubMed2005

An approach to investigating the importance of high potency polycyclic aromatic hydrocarbons (PAHs) in the induction of lung cancer by air pollution.

Evidence suggests that people living in urban areas have an increased risk of lung cancer due to higher levels of air pollution in these areas. Benzo[a]pyrene (B[a]P) is currently used as the main indicator of carcinogenic polycyclic aromatic hydrocarbons (PAHs) in air pollution, but there is concern that B[a]P may not be the ideal surrogate of choice for PAH mixtures since higher potency PAHs have recently been identified which could potentially contribute more and variably to the overall carcinogenicity. Dibenzo[a,h]anthracene (DBA) and dibenzo[a,l]pyrene (DB[a,l]P) are estimated to have carcinogenic potencies 10 or more times greater than B[a]P but data on their presence and formation in the environment are limited. Several occupational and environmental PAH biomonitoring studies are reviewed here, with particular focus on the specific exposure groups, study design, sample tissue, in particular the use of nasal tissues, and biomarkers used in each study. Consideration of these data is then used to propose a novel biomonitoring approach to evaluate exposure, uptake and the role of high potency PAHs in air pollution-related lung cancer. This is based upon an occupational study examining specific DNA adducts for DBA and DB[a,l]P in nasal cells to evaluate the extent to which these high potency PAHs might contribute to the increased risk of developing lung cancer from air pollution.

Air↗
PubMed2004

Approaches to carcinogenic risk assessment for polycyclic aromatic hydrocarbons: a UK perspective.

This paper reviews the approaches to carcinogenic risk assessment of polycyclic aromatic hydrocarbons (PAHs) in air pollution with emphasis on high potency PAHs such as dibenzo[a,l]pyrene (DB[a,l]P). The potency of DB[a,l]P may be 100-fold greater than benzo[a]pyrene (B[a]P); thus the B[a]P surrogate approach currently used to monitor for compliance with UK air pollution standards may not be appropriate. It is suggested that an approach based on potency equivalency factors (PEFs) could be developed to include highly potent PAHs provided an appropriate reference data set for relevant PAHs using a route acceptable for inhalation risk assessment is selected. Available data suggest that intratracheal administration of low doses of PAHs to rats is likely to simulate the kinetics of inhalation exposure to PAHs in a feasible manner. The use of a measure of total DNA adducts as an endpoint, which correlates well with lung tumourigenicity, would provide surrogate data for setting PEFs without the need for long-term bioassays in rodents. Further, dose-response studies using intratracheal administration of a range of PAHs singly and in combination to assess additivity are required to develop a PEF system for inhalation PEFs derived from DNA adduct measurements.

Air Pollutants↗
PubMed2002

Cancer Research UK procedures in manufacture and toxicology of radiotracers intended for pre-phase I positron emission tomography studies in cancer patients.

Radiolabelled compounds formulated for injection (radiopharmaceuticals), are increasingly being employed in drug development studies. These can be used in tracer amounts for either pharmacokinetic or pharmacodynamic studies. Such radiotracer studies can also be carried out early in man, even prior to conventional Phase I clinical testing. The aim of this document is to describe procedures for production and safety testing of oncology radiotracers developed for imaging by positron emission tomography in cancer patients. We propose strategies for overcoming the inability to produce compounds in sufficient quantities via the radiosynthetic routes for full chemical characterisation and toxicology testing including (i) independent confirmation as far as possible that the stable compound associated with the radiopharmaceutical is identical to the non-labelled compound, (ii) animal toxicity studies with > or = 10 times (typically 100 times) the intended tracer dose in humans scaled by body surface area, and (iii) patient monitoring during the radiotracer positron emission tomography clinical trial.

Animals↗
PubMed2002

Cytochrome P450 expression in human hepatocytes and hepatoma cell lines: molecular mechanisms that determine lower expression in cultured cells.

1. Cultured hepatic cells have reduced cytochrome P450 (CYP) activities in comparison with human liver, but the mechanism(s) that underlies this circumstance is not clear. We investigated the causes of this low CYP activity by analysing the activity, protein, mRNA and heterologous nuclear RNA contents of the most important CYPs involved in drug metabolism (1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5) in cultured human hepatocytes, and in HepG2 and Mz-Hep-1 hepatoma cell lines. 2. After 24 h of culture, hepatocytes retained most of their CYP activities and protein contents, but the mRNA decreased 20-fold. However, the mRNA content of most CYPs in 24-h hepatocytes was still 400-fold higher than in hepatoma cells. When we examined the transcriptional activity of the CYP genes, this decreased during culture time in hepatocytes and it was poor in hepatoma cell lines. 3. We investigated the abundance of key hepatic transcription factors that govern CYP transcription (C/EBP-beta: LAP and LIP, HNF-3alpha, HNF-4alpha, RXR-alpha) and observed that the expression of some factors was altered in the hepatoma cells. 4. In conclusion, the loss of biotransformation activity in cultured hepatic cells is caused by a decrease in CYP transcription, which correlates with an alteration in the expression of key transcription factors.

Blotting, Western↗
PubMed2002

Current knowledge and recent developments in consumer exposure assessment of pesticides: a UK perspective.

Techniques employed in the assessment of consumer exposure to pesticides are currently being reviewed in the UK. This is not a formal process as is happening in the USA. However, the advent of probabilistic approaches and sophisticated computer models has prompted regulators, industry and other stakeholders in the UK to recognize the need for refinements in the risk-assessment process. Sources of information and data necessary to explore such refinements are disparate. This review aims to collate the information to present a coherent picture of the current knowledge, the data available and the stakeholders involved. It can then be used as a resource with which to investigate further more specific issues. Although focussing on the UK, the European context is included and reference is made to US models and developments that should be investigated. Factors hampering progress include the lack of sufficient data on which to base quantitative analysis, especially in the residential pesticides sector, and lack of experience in using and interpreting probabilistic models. At present, such techniques are being approached with some caution in the UK and in Europe, although their utility for cumulative assessment is accepted. Communicating results to both risk managers and consumers will be a considerable challenge.

Community Participation↗
PubMed1999

Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways.

The aim of this study was to re-examine the human hepatic metabolism of diclofenac, with special focus on the generation of minor hydroxylated metabolites implicated in the idiosyncratic hepatotoxicity of the drug. Different experimental approaches were used: human hepatocytes, human microsomes, and engineered cells expressing single human CYP (cytochromes P450). Human hepatocytes formed 3'-hydroxy-, 4'-hydroxy-, 5-hydroxy- 4',5-dihydroxy-, and N,5-dihydroxydiclofenac, as well as several lactams. Formation of 4'- and 5-hydroxydiclofenac by human liver microsomes followed a Michaelis-Menten kinetics (Km 9 +/- 1 microM; Vmax 432 +/- 15 pmol/min/mg and Km 43 +/- 5 microM; and Vmax 15.4 +/- 0.6 pmol/min/mg, respectively). Secondary metabolites were detected after incubation of 5-hydroxydiclofenac with human liver microsomes, yielding 4',5-dihydroxydiclofenac (Km 15 +/- 1 microM; Vmax 96 +/- 3 pmol/min/mg) and small amounts of N,5-dihydroxydiclofenac (non-Michaelis-Menten kinetics). Based on microsome studies and the incubations with human hepatocytes and engineered cells, we estimated that in vivo CYP2C9 would be exclusively responsible for the 4' hydroxylation of diclofenac (>99.5%) as well as 5-hydroxydiclofenac (>97%). CYP2C9 was exclusively responsible for the formation of 3'-hydroxydiclofenac. Multiple regression analysis evidenced that the rate of production of 5-hydroxydiclofenac in human microsomes followed the algorithm: 0.040 x S-mephenytoin 4'-hydroxylation + 0.083 x tolbutamide methylhydroxylation, (multiple correlation coefficient = 0.969). However, the incubation of diclofenac with cell lines expressing different human CYP suggested that 7 isoforms could be involved. Comparison of data obtained with CYP-expressing cells and human hepatocytes suggests that CYP2C8 > CYP2C19 approximately CYP2C18 >> CYP2B6 are the isoforms implicated in the 5-hydroxylation of diclofenac in vivo.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Expression of xenobiotic-metabolizing CYPs in human pulmonary tissue.

The pattern of expression of individual cytochrome P450 (CYP) forms participating in the metabolism of xenobiotics is being increasingly well characterised in the human pulmonary tissue. Recent studies using methods having increased sensitivity and specificity, such as the reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, have revealed constitutive and inducible expression of several CYP forms in different cell types of the human lung. These studies have revealed the presence of mRNA of several procarcinogen-activating CYP forms in whole lung tissue and alveolar macrophages, including CYP1A1, CYP2B6/7, CYP2E1, and CYP3A5. The results of several studies on CYP2D6 expression have yielded contradictory results. Immunohistochemical analysis shows that CYP3A5 protein is present in all lung samples studied, and is localized in the ciliated and mucous cells of the bronchial wall, bronchial glands, bronchiolar ciliated and terminal cuboidal epithelium, type I and type II alveolar epithelium, vascular and capillary endothelium, and alveolar macrophages. Also CYP3A4 protein is found in some cell types in a minority (about 20%) of lung samples. Primary cultures of freshly isolated broncho-alveolar macrophages as well as a continuously growing bronchial carcinoma cell line (A-549) are being used for CYP induction studies in our laboratory. The results indicate that CYP1 family members are inducible in these cells by polycyclic aromatic hydrocarbon (PAH) inducers, and that CYP3A5, but not CYP3A4, is present constitutively. The results of these studies indicate that several different xenobiotic-metabolizing CYPs are present in the human lung and lung-derived cell lines, possibly contributing to in situ activation of pulmonary procarcinogens. Interindividual differences in the expression of these CYPs may contribute to the risk of developing lung cancer and possibly other pulmonary diseases initiated by agents that require metabolic activation.

Cells, Cultured↗
PubMed1998

Expression of xenobiotic-metabolizing cytochrome P450s in human pulmonary tissues.

The purpose of the study was to obtain a comprehensive picture of the expression of cytochrome P450s (CYP) in the human lung, broncho-alveolar macrophages (BAM), and peripheral blood lymphocytes. The methods used were reverse transcriptase-polymerase chain reaction (RT-PCR) with gene-specific primers and immunohistochemistry with specific anti-peptide antibodies. In RT-PCR, CYPs 1A1, 2B6/7, 2E1, 2F1, 3A5 and 4B1 were detected in cDNA prepared from whole lung tissue. BAMs expressed CYPs 1B1, 2B6/7, 2C, 2E1, 2F1, 3A5 and 4B1. These tissues lacked CYPs 1A2, 2A6, 2D6, and 3A7. In peripheral blood lymphocytes, only CYP1B1 and CYP2E1 mRNAs were consistently detected. In immunohistochemistry with anti-CYP3A antibodies, epithelial staining of CYP3A5 was observed in 100% of individuals, while only about 20% exhibited CYP3A4 staining. CYP3A5 protein was localized in the bronchial wall, bronchial glands, bronchiolar epithelium, alveolar epithelium, vascular endothelium and alveolar macrophages. The results indicate that several different xenobiotic-metabolizing CYPs are present in the human lung, possibly contributing to in situ activation of pulmonary procarcinogens.

Cytochrome P-450 Enzyme System↗
PubMed1992

Pharmacokinetics of [14C]FCE 22891, a penem antibiotic, following oral administration to healthy volunteers.

FCE 22891 is a prodrug of the penem antibiotic FCE 22101 and is suitable for oral administration. The pharmacokinetics of FCE 22891 were investigated in four healthy male volunteers following the oral administration of 500 mg of [14C]FCE 22891. Levels of radioactivity in plasma were always higher and persisted for longer than those of FCE 22101. The time to the maximum concentration of radioactivity in plasma generally coincided with that of FCE 22101. The respective values for the maximum concentrations of radioactivity in plasma were, on average, 8.57 +/- 2.95 micrograms equivalent/ml and 2.97 +/- 2.05 micrograms/ml. Over a 5-day period, mean urinary and fecal recovery of radioactivity accounted for 53.2 and 41.0% of the dose, respectively. The average amount of FCE 22101 excreted in urine and feces corresponded to 9.0 and 1.6% of the dose, respectively. The urinary recovery of the open-ring metabolite P1 and of its 5-S epimer P2 accounted for about 6.5 and 1.2% of the dose, respectively. Other chromatographic peaks corresponding to nonidentified compounds accounted for about 14.0% (polar metabolite fraction; peak P), 3.7% (less polar fraction; peak X), and 15.4% (least polar fraction) of the dose. Elimination of radioactivity and FCE 22101 in urine was rapid. Intersubject variability in the kinetics of total radioactivity in plasma was far less than that observed for FCE 22101. The results of the present study support suggestions that presystemic metabolism of FCE 22101 and/or transformation of the prodrug to compounds other than FCE 22101 are the main cause of intersubject variability in the kinetics of FCE 22101 produced in plasma following oral administration of its prodrug.

Administration, Oral↗
PubMed1980

Catecholamine turnover in essential hypertension.

With the more widespread use of sensitive specific methods of measurements of catecholamines and metabolites, more emphasis must be given to assessment of dynamic indices of catecholamine turnover. Wide inter-individual differences in noradrenaline clearance from plasma and in resting endogenous production rate, together with individual differences in responsiveness, frustrate simplistic attempts to relate plasma level of transmitter with turnover. To assess catecholamine function adequately plasma and urinary levels of catecholamine and the main metabolites should be determined together with an index of responsiveness. Central nervous catecholamine turnover cannot be easily assessed from measurement of urinary metabolite excretion Cerebrospinal fluid concentration of MHPG may provide an index of brain noradrenaline turnover.

Blood Pressure↗
PubMedDate not supplied

Methods of in vitro toxicology.

In vitro methods are common and widely used for screening and ranking chemicals, and have also been taken into account sporadically for risk assessment purposes in the case of food additives. However, the range of food-associated compounds amenable to in vitro toxicology is considered much broader, comprising not only natural ingredients, including those from food preparation, but also compounds formed endogenously after exposure, permissible/authorised chemicals including additives, residues, supplements, chemicals from processing and packaging and contaminants. A major promise of in vitro systems is to obtain mechanism-derived information that is considered pivotal for adequate risk assessment. This paper critically reviews the entire process of risk assessment by in vitro toxicology, encompassing ongoing and future developments, with major emphasis on cytotoxicity, cellular responses, toxicokinetics, modelling, metabolism, cancer-related endpoints, developmental toxicity, prediction of allergenicity, and finally, development and application of biomarkers. It describes in depth the use of in vitro methods in strategies for characterising and predicting hazards to the human. Major weaknesses and strengths of these assay systems are addressed, together with some key issues concerning major research priorities to improve hazard identification and characterisation of food-associated chemicals.

Animal Testing Alternatives↗