The role of cell proliferation in chemically induced carcinogenesis.
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Animals↗
Biomedical subjects
J R Foster
Publications and source records attributed to J R Foster.
Successful coping, adaptation and resilience in the elderly: an interpretation of epidemiologic data.
The elderly are often thought to suffer inevitable declines in functional abilities due to normal aging and concomitant diseases (acute and chronic). This view may be true for many aspects of physical health. However, an abundance of evidence suggests that mental health diverges from physical health in that Coping, Adaptation and Resilience (CAR) functions are surprisingly well-preserved throughout most of the life span. The normal "anatomy" and "physiology" of the CAR construct is described. It's robust relationship with the abnormalities of DSM-IV geriatric mental disorders is illustrated. Opportunities for new approaches to treatment are noted. These insights from the elderly are applicable to all age groups.
Adaptation, Psychological↗
Audiometer calibration: two neglected areas.
British and International Standards for pure tone audiometry require that the static force exerted by the earphone/bone vibrator headband is within certain limits. However, no recommended procedure is given for making force measurements. In addition, standards for audiometers require that linearity of output level is within certain limits. Only a brief outline of a procedure is available for measuring linearity at low intensity levels. Both these areas of audiometer calibration tend to be neglected according to our survey of organizations offering calibration services. Equipment and protocols for measuring both have been developed at the MRC Institute of Hearing Research, and are described. A convenience sample of audiometers gave a wide range of headband forces, many of which do not comply with the relevant standard. Linearity of output at low levels did comply with the relevant standard for all audiometers measured. We recommend the use of simple devices, such as those described, for routine calibration. They are quick and easy to use, give reliable results, and are inexpensive.
Acoustics↗
The distribution of theta-class glutathione S-transferases in the liver and lung of mouse, rat and human.
Two murine Theta-class glutathione S-transferases (GSTs), mGSTT1 and mGSTT2, have been cloned and sequenced. The murine cDNAs, together with the published sequences of the rat and human enzymes, were used to design oligonucleotide probes in order to determine the distribution of mRNA for these enzymes in the liver and lung of rat, mouse and human. The mRNA distribution was compared with that of enzyme protein determined with an antibody to rat GSTT2-2. Both the antibody and the oligonucleotide probes gave the same distribution patterns. Both enzymes were present at significantly higher concentrations in mouse tissues than in rat or human tissues. In mouse liver, both enzymes were localized in specific cell types and in nuclei. Although the distribution of GSTT2-2 in rat liver was similar to that seen in the mouse, GSTT1-1 was not localized in a specific cell type or in the nuclei of either rat or human liver. In the lungs, very high concentrations of the Theta enzymes were present in mouse-lung Clara cells and ciliated cells, with much lower levels in the Clara cells only of rat lung. Low levels of human transferase GSTT1-1 were detected in a small number of Clara cells and ciliated cells at the alveolar/ bronchiolar junction. The relative activities between species, and the cellular and sub-cellular distribution within the liver and lungs of each species, provides an explanation for the species-specificity of methylene chloride, a mouse-specific carcinogen activated by glutathione S-transferase GSTT1-1.
Animals↗
Measures of cell replication in risk/safety assessment of xenobiotic-induced, nongenotoxic carcinogenesis.
The phenomena associated with nongenotoxic carcinogenesis are multifaceted and complex. Nongenotoxic carcinogens stimulate cell replication in the presence or the absence of cytotoxicity. Cell proliferation is pivotal in the neoplastic process, but the extent of its contribution to the development of xenobiotic-induced cancer remains an open question. The search for a better understanding of this process has generated considerable interest and effort, often with the objective of obtaining useful predictors of the tumourigenic potential of xenobiotics. Alterations in the natural balance of endogenous humoural agents that maintain replicative homeostasis results in proliferative stimulation (or inhibition) which may be transient or sustained. The bases for the molecular interaction of these mediators with cellular receptors, trans-cytoplasmic message conveyance, and subsequent nuclear responses leading to xenobiotic-induced mitosis are becoming better understood. Assessment of tissue replicative status has now become established and utilizes biochemical and histological methodology in a routine manner. The increasingly challenging international regulatory environment is demanding greater understanding of the mechanisms that underlie fundamental phenomena and the influences exerted by xenobiotics prior to their registration. While the precise mode of action of an individual xenobiotic may not be known, sound interpretation of toxicological data, including the contribution made by cell replication, creates greater confidence of its safety in the scientific, regulatory, and commercial communities. This article offers a view of cell proliferation from molecular interactions at the cellular level, through practical assessment of cell and tissue replicative status to its utility in contributing to the registration of new drugs and chemicals.
Biological Assay↗
Peroxisomes without catalase: more evidence for the active oxygen hypothesis?
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Animals↗
Methylene chloride: an inhalation study to investigate toxicity in the mouse lung using morphological, biochemical and Clara cell culture techniques.
Single exposures of mice to methylene chloride (MC) cause vacuolation and necrosis of the bronchiolar Clara cells which subsequently recover normal morphology on continued exposure. Both cytochrome P-450 (CYP)- and glutathione S-transferase (GST)-dependent metabolism of MC are known to occur. The current studies have investigated the metabolism of MC in mouse lung using inhibitors of both GST and CYP-dependent routes of metabolism, the consequences of metabolic inhibition on the Clara cell vacuolation, and any changes in cell proliferation, assessed in vitro, in Clara cells cultured from exposed individuals. Vacuolated bronchiolar cells were seen in mice exposed to 2000 and 4000 ppm MC but were not seen at lower concentrations, while addition of the CYP inhibitor, piperonyl butoxide, significantly reduced the bronchiolar cell vacuolation seen following exposure to 2000 ppm MC. Treatment of mice with the glutathione depletor, buthionine sulphoximine, had no effect on the number of vacuolated bronchiolar cells following MC. Exposure of mice to 1000 ppm MC and above for 6 h caused a burst of DNA synthesis in bronchiolar Clara cells cultured in vitro from the lungs of exposed animals. The results suggest that the Clara cell vacuolation following MC exposure is mediated via CYP metabolism, that depression of the CYP metabolic pathway occurs following exposure, and that Clara cell vacuolation may have a priming role in stimulating cell proliferation in the unaffected cell population.
Administration, Inhalation↗
Nephrotoxicity of 4-amino-3-S-glutathionylphenol and its modulation by metabolism or transport inhibitors.
The nephrotoxicity of 4-amino-3-S-glutathionylphenol (PAP-GSH), a known metabolite of 4-amino-phenol (PAP), was determined in male Fischer 344 rats. Administration of a single dose of 40 or 60 mumol kg-1 caused a marked elevation in blood urea nitrogen and an increase in the urinary excretion of glucose, protein and gamma-glutamyltransferase (GGT). These changes were associated with histological alterations in the proximal tubule, where at the lower dose the lesion was restricted to the S3 region of the proximal tubule in the medullary rays, while at the higher dose the lesion extended to affect the S3 region in both the medullary rays and the outer stripe of the outer medulla. Studies with [35S]-PAP-GSH at 40 mumol kg-1 showed selective retention of radioactivity in the kidney, relative to other organs 24 h after dosing and that some radioactivity was covalently bound to renal proteins. Pretreatment of animals with probenecid, an inhibitor of renal organic anion transport, or aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, had little or no effect on the toxicity. In contrast, pretreatment of animals with acivicin, an inhibitor of gamma-glutamyltransferase, or co-administration of PAP-GSH with ascorbic acid almost completely protected against the nephrotoxicity. This protection was associated with a decreased concentration of radioactivity from [35S]-PAP-GSH in the kidneys and a decrease in the amount covalently bound to renal protein. Thus, the nephrotoxicity of PAP-GSH may be mediated by oxidation and further processing of the glutathione conjugate via gamma-glutamyltransferase.
Aminooxyacetic Acid↗
Immunohistochemical localisation of six glutathione S-transferases within the nasal cavity of the rat.
Many xenobiotics induce lesions within the nasal cavity of experimental animals which are site specific. This site selectivity may be due to regional deposition within the nasal cavity and/or the localisation of biotransformation enzymes. We have developed methodology which allows immunohistochemical localisation of xenobiotic biotransformation enzymes in transverse sections of the rat nasal cavity identical to those normally taken for pathological examination. We report the application of this methodology to six isoenzymes of the glutathione S-transferases (GSTs). All six isoenzymes were predominantly located within olfactory epithelium covering the ethmoturbinates (levels III and IV) and extending forwards into the dorsal meatus (level II). Squamous and transitional epithelia showed little or no staining while respiratory epithelium was weakly stained. Within the respiratory epithelium only the ciliated columnar cells and, to a lesser extent, some of the seromucous glands contained GSTs. Within olfactory epithelium the sustentacular cells, basal cells and subepithelial glands all stained positive for GSTs. The different cell types of olfactory epithelium preferentially express different GST isoenzymes: 1-1 and 2-2 were predominantly located in the subepithelial glands; 3-3, 4-4 and 8-8 in sustentacular and basal cells; 7-7 in basal cells.
Animals↗
Image analysis of bromodeoxyuridine (BrdU) staining for measurement of S-phase in rat and mouse liver.
We developed a system for quantifying the numbers of bromodeoxyuridine (BrdU)-labeled hepatocyte nuclei in rat and mouse liver with an automated image analysis system. We began by developing a protocol for BrdU staining that would provide consistently intense staining to facilitate identification of both labeled and unlabeled nuclei by image analysis. Preliminary studies detected and characterized hepatocyte nuclei and differentiated them from non-hepatocyte nuclei using area and form factors. The parameters were selected to optimize discrimination between the two populations, selecting 90% of hepatocyte and 5% non-hepatocyte nuclei. Finally, we developed a program for automatic counting of BrdU-labeled hepatocyte and total hepatocyte nuclei. Results obtained from this method correlated well with data collected by a microscopist over a wide range of labeling indices. The automated system reduces interobserver variation and should minimize intraobserver error, as well as reducing the tedium of measuring labeling indices in the liver. Moreover, the techniques described should be applicable to other tissues.
Animals↗
Clinical evaluation and test-retest reliability of the IHR-McCormick Automated Toy Discrimination Test.
The IHR-McCormick Automated Toy Discrimination Test (ATT) measures the minimum sound level at which a child can identify words presented in quiet in the sound field. This 'word-discrimination threshold' provides a direct measure of the ease with which a child can identify speech and a surrogate measure of auditory sensitivity. This paper describes steps taken to maximize the test-retest reliability of the ATT and to enable it to measure word-discrimination thresholds in noise as well as in quiet. It then describes the results of a clinical evaluation of the ATT in which paediatric audiologists measured word-discrimination thresholds in quiet from 215 successive attendees (in the age range 2 to 13 years) at a paediatric audiology clinic presenting over a 2-month period. When children with atypical cognition or delayed development of language were excluded, 72% of the children provided two word-discrimination thresholds and 83% provided at least one word-discrimination threshold. Children who failed to provide word-discrimination thresholds were generally younger than four years of age. Although a few children who could not perform pure-tone or warble-tone audiometry managed to provide word-discrimination thresholds, most children who could perform the ATT could also perform pure-tone audiometry. The average pure-tone threshold in the better-hearing ear could be predicted from the word-discrimination threshold with a 95% confidence interval of +/- 13 dB. The test-retest reliability of the ATT was measured in two ways. First, to enable comparison with published results, the within-subjects standard deviation of word-discrimination thresholds was calculated. It varied as a function of age and degree of impairment, but was never worse than 3.3 dB. Children of four years of age and older displayed the adult reliability of 2.3 dB. Second, the variability of absolute differences between word-discrimination thresholds was calculated. It was such that a change of 7 dB between two runs of the test (e.g. aided and unaided) would be expected to occur by change less than one time in 20. These results extend previous evaluations of the ATT to a clinically representative population and confirm that word-discrimination thresholds provide a useful complement to warble-tone and pure-tone audiometry.
Adolescent↗
Juxtaposition of peroxisomes and chromosomes in mitotic hepatocytes following methyl clofenapate administration to rats.
Administration of 25 mg/kg/day methyl clofenapate to Alpk/APfSD rats for up to 4 days gave rise to hepatomegaly resulting from a combination of hepatocyte hyperplasia, mainly in the periportal region of the lobule, and centrilobular cell hypertrophy. In hepatocytes undergoing mitosis there was a redistribution of dense vesicles and some peroxisomes to the perinuclear region of the cytoplasm. With increasing length of exposure to methyl clofenapate the number of peroxisomes located in this region during mitosis increased. Chromosomes observed by electron microscopy were seen to lie in close apposition to these organelles. Immunocytochemical localization of the Phase II conjugating enzymes glutathione-S transferase B, C and E showed a dramatic reduction and redistribution of those enzymes in mitotic cells and their absence in the region of the chromosomes. These events may increase the vulnerability of DNA to damage in specific cells.
Animals↗
Stratification of sudden death risk in patients receiving long-term amiodarone treatment for sustained ventricular tachycardia or ventricular fibrillation.
One hundred twenty-two patients treated chronically with amiodarone for sustained ventricular tachycardia or ventricular fibrillation after failing conventional antiarrhythmic therapy were analyzed to determine which factors were predictive of sudden cardiac death during follow-up. The mean left ventricular ejection fraction in the study group was 0.32, and 87% of the patients had coronary artery disease with a prior myocardial infarction. During a median follow-up of 19.5 months, 30 patients died suddenly. The only variable that was predictive of sudden death was left ventricular ejection fraction. Twenty-nine of the 84 patients with ejection fractions < 0.40 died suddenly, compared with 1 of 35 patients with ejection fractions > or = 0.40. The actuarial probability of sudden death at 5 years was 49% when the ejection fraction was < 0.40, and 5% when the ejection fraction was > or = 0.40 (p = 0.0004). These results indicate that patients treated with amiodarone for sustained ventricular tachycardia or ventricular fibrillation whose ejection fractions are > or = 0.40 are at low risk for sudden death. Patients with ejection fractions < 0.40 remain at high risk for sudden death, and should be considered for additional or alternative therapy.
Actuarial Analysis↗
Induction of drug-metabolizing enzymes in human pancreatic cancer and chronic pancreatitis.
Chronic pancreatitis and pancreatic cancer have both been linked with occupational exposure to organic chemicals. These chemicals are known to be metabolized within the liver by the cytochrome P-450 family of enzymes, and indeed are able to induce levels of these enzymes as evidence of their interaction. The purpose of this study was therefore to see if these enzyme systems were altered in chronic pancreatitis and pancreatic cancer. Immunocytochemistry of four phase I drug-metabolizing enzymes (cytochromes P-450 IIIA1, P-450 IIE, P-450 IA2, and NADPH cytochrome P-450 oxido-reductase) and one phase II enzyme [glutathione S-transferase (GST) 5-5] was therefore performed on pancreas and/or liver biopsy samples from organ donors and compared with patients with chronic pancreatitis or pancreatic cancer. In samples from donor subjects, the types and levels of drug-metabolizing enzymes in hepatocytes were similar to those seen in pancreatic acinar cells. In material from patients with chronic pancreatitis or pancreatic cancer, cytochrome P-450 enzyme levels were greater in both the liver and the pancreas than those seen in the donor group, while GST levels were unchanged. Islets of Langerhans showed high levels of P-450 IA2 in the donor group, with clear induction of P-450 IIIA1 and NADPH cytochrome P-450 oxidoreductase in patients with chronic pancreatitis but not in the pancreatic cancer group. Levels of GST 5-5 were also induced in the islets. The present findings raise the possibility of an aetiological relationship between elevated levels of drug-metabolizing enzymes and the subsequent development of disease.
Aryl Hydrocarbon Hydroxylases↗
Effect of ascorbic acid, acivicin and probenecid on the nephrotoxicity of 4-aminophenol in the Fischer 344 rat.
4-Aminophenol (p-aminophenol, PAP) causes selective necrosis to the pars recta of the proximal tubule in Fischer 344 rats. The basis for this selective toxicity is not known but PAP can undergo oxidation in a variety of systems to form the 4-aminophenoxy free radical. Oxidation or disproportionation of this radical will form 1,4-benzoquinoneimine which can covalently bind to cellular macromolecules. We have recently reported that a glutathione conjugate of PAP, 4-amino-3-S-glutathionylphenol, is more toxic to the kidney than the parent compound itself. In this study we have examined the distribution and covalent binding of radiolabel from 4-[ring 3H]-aminophenol in the plasma, kidney and liver of rats 24 h after dosing and related these findings to the extent of nephrotoxicity. In addition, we have examined the effect of ascorbic acid which will slow the oxidation of PAP; acivicin, an inhibitor of gamma-glutamyltransferase and hence the processing of glutathione-derived conjugates; and probenecid, an inhibitor of organic anion transport on the nephrotoxicity produced by PAP. Administration of a single dose of PAP at 458 or 687 mumol kg-1 produced a dose-related alteration in renal function within 24 h which was associated with proximal tubular necrosis. The lesion at the lower dose was restricted to the S3 proximal tubules in the medullary rays, while at the higher dose it additionally affected the S3 tubules in the pars recta region of the cortex.(ABSTRACT TRUNCATED AT 250 WORDS)
Aminophenols↗
Ontogenetic development of the distribution of constitutive and 3-methylcholanthrene-induced CYP1A1 and CYP1A2 in rabbit liver.
We investigated the expression, distribution, and inducibility of 3-methylcholanthrene (MC)-inducible P450 enzymes, CYP1A1 and 1A2, in livers of rabbits at different stages of development, ranging from 4 days before birth (-4 days of age) to adulthood. These enzymes were identified by immunoblotting and immunocytochemistry and quantified by dot-blotting, utilizing previously characterized monoclonal antibodies, 107 and 3/4/2, specific for CYP1A2 and both CYP1A1 and 1A2, respectively, and a polyclonal antibody that recognizes both enzymes. Expression of CYP1A2 is always greater than that of CYP1A1 in livers of untreated rabbits, regardless of age. Moreover, immunocytochemistry showed that CYP1A1 is evenly distributed throughout the liver at all ages, whereas CYP1A2 is highly localized to only a few scattered cells at 1 day before birth. More hepatocytes express this enzyme perinatally. By 6 days of age, expression of CYP1A2 is confined to a narrow band of centrilobular cells, but with increasing age the enzyme is expressed in more hepatocytes until weaning, when all hepatocytes are positive. Although CYP1A1 is induced by MC treatment at most ages, there is no change in its distribution. In contrast, induction of CYP1A2 was shown immunocytochemically to occur in only a limited number of hepatocytes in fetal rabbits. There is a progressive increase with age in the number of hepatocytes that are inducible for CYP1A2. The greatest fold-induction of hepatic CYP1A2 by MC in the rabbit is a 9-11 days of age, when, for MC-treated rabbits, CYP1A2 represents > 60% of the total P450 pool. The modulation of enzyme expression caused by MC treatment of fetuses/neonates leads to developmentally advanced livers with respect to P450 and could have a significant impact on the fetal and neonatal toxicity of some foreign compounds. These data demonstrate, for the first time, that the ontogenetic expression and localization of CYP1A1 and 1A2 within the liver are differentially regulated at the level of the individual cell.
Aging↗
Lip-reading the BKB sentence lists: corrections for list and practice effects.
Two groups of 21 adult subjects with normal hearing viewed the video recordings of the Bamford-Kowal-Bench standard sentence lists issued by the EPI Group in 1986. Each subject viewed all of the 21 lists and attempted to write down the words contained in each sentence. One group lip-read the lists with no sound (the LR:alone condition). The other group also heard a sequence of acoustic pulses which were synchronized to the moments when the talker's vocal folds closed (the LR&Lx condition). Performance was assessed both by loose (KW(L)) and by tight (KW(T)) keyword scoring methods. Both scoring methods produced the same pattern of results: performance was better in the LR&Lx condition; performance in both conditions improved linearly with the logarithm of the list presentation order number; subjects who produced higher overall scores also improved more with experience of the lists. The data were described well by a logistic regression model which provided a formula which can be used to compensate for practice effects and for differences in difficulty between lists. Two simpler, but less accurate, methods for compensating for variation in inter-list difficulty are also described. A figure is provided which can be used to assess the significance of the difference between a pair of scores obtained from a single subject in any pair of presentation conditions.
Adolescent↗
A mechanism for the development of Clara cell lesions in the mouse lung after exposure to trichloroethylene.
Female CD-1 mice exposed to trichloroethylene (6 h/day) at concentrations from 20-2000 ppm developed a highly specific lung lesion after a single exposure, characterised by vacuolation of the Clara cells, the number of cells affected increasing with increasing dose level. At the highest dose levels pyknosis of the Clara cells was apparent. After 5 days of repeated exposures the lesion had resolved but exposure of mice following a 2-day break resulted in recurrence of the lesion. The changes in mouse lung Clara cells were accompanied by a marked loss of cytochrome P-450 activities. No morphological changes were seen in the lungs of rats exposed to either 500 or 1000 ppm trichloroethylene. Isolated mouse lung Clara cells were shown to metabolize trichloroethylene to chloral, trichloroethanol and trichloroacetic acid. Chloral was the major metabolite. Trichloroethanol glucuronide was not detected. In comparative experiments using mouse hepatocytes the major metabolites were trichloroethanol and its glucuronide conjugate. The activity of UDP-glucuronosyltransferase was compared in mouse lung Clara cells and hepatocytes using two phenolic substrates and trichloroethanol. Hepatocytes readily formed glucuronides from all three substrates whereas Clara cells were only active with the two phenolic substrates. The three major metabolites of trichloroethylene, chloral, trichloroethanol and trichloroacetic acid were each dosed to mice and of these metabolites, only chloral had an effect on mouse lung causing a lesion (Clara cell) identical to that seen with trichloroethylene. It is proposed that the failure of Clara cells to conjugate trichloroethanol leads to an accumulation of chloral which results in cytotoxicity. The known genotoxicity of chloral suggests that this lesion may be related to the development of lung tumours in mice exposed to trichloroethylene by inhalation.
Animals↗