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Biomedical subjects

W P Watson

Publications and source records attributed to W P Watson.

At least 19 recordsLinked to original sources
PubMed2004

Comparison of the metabolism of ethylene glycol and glycolic acid in vitro by precision-cut tissue slices from female rat, rabbit and human liver.

1. The metabolism of [1,2-(14)C]-ethylene glycol and [1,2-(14)C]-glycolic acid was studied in vitro using precision-cut tissue slices prepared from the livers of female Sprague-Dawley rats, New Zealand white rabbits and humans. The time-course for production of metabolites formed from ethylene glycol at concentrations from 3 to 40 mM was determined to compare quantitatively the differences between species in the rates and amounts of formation of glycolic acid, the presumed developmental toxicant of ethylene glycol. The rates of metabolism of glycolic acid to glyoxylic acid at concentrations from 0.05 to 16 mM by liver tissue from the different species were also determined. The apparent V(max)/K(m) for the metabolic conversions of ethylene glycol to glycolic acid and for glycolic acid to glyoxylic acid in liver tissue from the different species were obtained. 2. There were qualitative differences in the metabolic profiles and quantitative differences in the formation of glycolic acid between the mammalian liver systems. There was an average of 10-fold less glycolic acid produced by liver slices from rabbits compared with rats. With the human liver, the formation of glycolic acid was not detectable using tissue from three of four human donors. A low level of glycolic acid was detected in one liver slice incubation from one of the four subjects, but only at one extended time point; glyoxylate was detected with liver slices from all four humans. 3. Liver slices prepared from female Sprague-Dawley rats, female New Zealand White rabbits and three female human subjects all metabolized glycolic acid to glyoxylic acid. Human liver tissue was the most effective at further metabolizing glycolic acid to glyoxylic acid. The ratios of V(max)/K(m), representing the relative clearance of glycolic acid from liver tissue, were approximately 14:9:1 for human, rat and rabbit liver, respectively. 4. Precision-cut liver slices maintained in dynamic organ culture are good predictors of metabolism by liver tissue in vivo. The results of the present study therefore indicate that levels of glycolic acid, if formed in vivo, following exposures to similar concentrations of ethylene glycol, would be lower in humans than in rabbits and rats.

Adult↗
PubMed2002

Selectivity of the protective effects of dihydropyridine calcium channel antagonists against the ethanol withdrawal syndrome.

Four dihydropyridine calcium channel antagonists were compared for their ability to protect against the hyperexcitability produced in mice by withdrawal from chronic ethanol treatment and to protect against seizures due to bicuculline or pentylenetetrazol. Comparison was also made of their effects on locomotor activity, body temperature and motor co-ordination, and with the corresponding effects of the benzodiazepine, diazepam. Nitrendipine, nimodipine, nicardipine (at 50 and 10 mg/kg) and isradipine (at 10 and 4 mg/kg) decreased the withdrawal hyperexcitability, but showed no anticonvulsant action against either bicuculline or pentylenetetrazol. Diazepam (1.5 and 4 mg/kg) both protected against the withdrawal signs and decreased seizure incidence after bicuculline and pentylenetetrazol, although the latter effects were of shorter duration than those on the withdrawal signs. The four dihydropyridines decreased spontaneous locomotor activity, an effect which lasted up to 6 h. Only isradipine and diazepam had any ataxic actions at the doses tested. All the dihydropyridines had hypothermic actions, considerably shorter in duration than effects on withdrawal hyperexcitability, with little evidence of dose dependence, except for nicardipine, which had a larger, dose-related, hypothermic action. Of the four compounds, isradipine was more potent in terms of dose, but not any more selective for effectiveness against the withdrawal signs, than the other three dihydropyridines, and nicardipine was slightly less effective in protecting against the withdrawal signs. The results indicate that the anticonvulsant effects of the dihydropyridines were selective for ethanol withdrawal hyperexcitability, whereas diazepam showed no such selectivity.

Animals↗
PubMed2002

Low alcohol preference among the "high alcohol preference" C57/BL10 mice; factors affecting such preference.

The effects of age, ethanol concentration and minor stress on the variation in alcohol preference of C57 strain mice were determined. In two bottle choice tests, an older population of mice contained slightly more low-preference mice than a younger population. A wide range of ethanol preference was consistently seen in young mice for 8% and 6% ethanol, but the previously reported biphasic pattern of distribution was revealed only with 8% ethanol. Very few animals showed high preference for concentrations of 10% or 12% ethanol. Moving low alcohol preference mice to a new location (but not repeated cage changing or ultrasonic noise) significantly increased the alcohol preference. Exploratory locomotor activity did not correlate with the subsequent alcohol consumption. Blood and brain alcohol concentrations showed that the differences in alcohol preference were not due to differences in metabolism of ethanol. The C57 strain mice with low preference for alcohol provides a valuable model for the study of the effects of minor stress on alcohol consumption.

Acoustic Stimulation↗
PubMed2001

Studies on a model of long term alcohol drinking.

This study investigated the effects of a dihydropyridine calcium channel antagonist in a free drinking model previously reported to show increased and 'uncontrolled' drinking. The results showed, rather than the previously reported increase in consumption, a gradual decrease in alcohol intake over 9-18 months. When the alcohol was withdrawn from one group of rats after 55 weeks free choice, the animals showed no behavioural signs of physical withdrawal, but they did demonstrate the expected elevated ethanol intake on reintroduction to ethanol after 2 weeks abstinence. A second group of rats were given 62 weeks free choice access to ethanol in groups of four, then transferred to single housing and baseline drinking levels established. Intraperitoneal injections of nimodipine 5 mg/kg, 20 mg/kg or Tween vehicle were then given once daily. Nimodipine had no effect on ethanol intake of animals with continuous access to ethanol, or of those animals withdrawn from ethanol and then reintroduced after 2 weeks of abstinence. However the unexpectedly low alcohol intake may have prevented any effects of nimodipine being seen.

Alcohol Drinking↗
PubMed2001

Metabolism and molecular toxicology of isoprene.

Isoprene (2-methylbuta-1,3-diene) is a large-scale petrochemical used principally in the manufacture of synthetic rubbers. It is also produced by plants and trees and is the major endogenous hydrocarbon formed by mammals, probably from mevalonic acid. Isoprene is metabolised by mammals in processes that involve epoxidation by cytochrome P450-dependent monooxygenases to the isomeric mono-epoxides, (1-methylethenyl)-oxirane and 2-ethenyl-2-methyloxirane. Further metabolism of the mono-epoxides to mutagenic isoprene di-epoxides, (2, 2')-2-methylbioxiranes, can also occur. The oxidations to the mono- and di-epoxides occur enantioselectively and diastereoselectively. The mono-epoxides are hydrolysed enantioselectively to vicinal diols under catalysis by epoxide hydrolase. 2-Ethenyl-2-methyloxirane is also readily hydrolysed non-enzymatically. Because of the stereochemical possibilities for metabolites, the metabolism of isoprene is complex. The metabolism of isoprene by liver microsomes in vitro from a range of species including rat, mouse and human shows significant differences between species, strains and gender in respect of the diastereoselectivity and enantioselectivity of the metabolic oxidation and hydrolysis reactions. The impact of the extra methyl in isoprene on di-epoxide reactivity also appears to be critically important for the resulting biological effects. Isoprene di-epoxides may exhibit a lower cross-linking potential in vivo compared to butadiene di-epoxides. Differences in metabolism and reactivity of metabolites may be factors contributing to the significant differences in toxicological response to isoprene observed between species.

Animals↗
PubMed2001

A novel DNA adduct, originating from 1,2-epoxy-3,4-butanediol, is the major DNA adduct after exposure to [2,3-(14)C]-1,3-butadiene,[4-(14)C]-1,2-epoxy-3-butane.

1,3-Butadiene is a rodent carcinogen and its epoxide metabolites, 1,2-epoxy-3-butene (EB), 1,2-epoxy-3,4-butanediol (EBD), and 1,2:3,4-diepoxybutane (DEB) have been suggested as ultimate carcinogens. This study aimed at identification and quantification of DNA adducts in rats and mice following exposure to BD and its major metabolite EB to identify the reactive epoxide(s) in target tissues. Reaction of [4-(14)C]-EB with 2'-deoxyguanosine (dG) or DNA gave equal amounts of N7-(2-hydroxy-3-butenyl)guanine (G1) and N7-(1-(hydroxymethyl)-2-propenyl)guanine (G2). Reaction of DEB stereomers with dG yielded N7-(2,3,4-trihydroxybutyl)guanine (G3) as major adduct and novel, minor adduct (G4) that was tentatively identified as N7-(1-(hydroxymethyl)-2,3-dihydroxypropyl)guanine. For the stereomers of EBD, the opposite was found: reaction with dG led to G4 as major and G3 as minor adduct. 2D-Total correlation 1H-NMR spectroscopy of G4 indicated that the N7-alkyl group was in a virtually fixed conformational state and might interact with the O(6) of guanine, which might imply a higher degree of mutagenicity of G4, due to G-C mispairing, than of any other adducts observed in this study. At 48 h following exposure to [4-(14)C]-EB (1-50 mg/kg), DNA adduct profiles in rat and mouse were qualitatively similar, with G1 and G2 as main, and G4 as minor adduct. Following nose-only exposure to 200 ppm [2,3-(14)C]-BD for 6 h, G1 and G2 were minor adducts in liver (1.9 and 8.0 per 10(8) nucleotides) and lung (1.6 and 6.6 per 10(8) nucleotides, for rats and mice, respectively). G3 was absent in rats, but present in mouse liver and lung, at 20 and 12 adducts/10(8) nucleotides. The major adduct was G4 accounting for 13 and 90 (liver) and 11 and 139 (lung) adducts/10(8) nucleotides in rats and mice, respectively. Forty-two hours later, these adduct levels had only little changed. Our recent biomarker studies confirm that following exposure to BD, but not BDO, EBD is the major epoxide available for macromolecular binding in humans and rodents. Most probably because EBD is in contrast to EB and DEB, a poor substrate for epoxide hydrolases. In conclusion, the major DNA adduct following exposure to BD is G4, originating from EBD, and not from EB or BDE. It is concluded that EBD and G4 should be taken into account for human risk assessment for exposure to BD.

Animals↗
PubMed2001

Chronic infusion of nicotine can increase operant self-administration of alcohol.

Effects of nicotine, administered by continuous infusion via osmotic minipumps, were studied on the operant self-administration of alcohol by rats, using a variable interval (15 s) schedule, and measuring the acquisition, maintenance, extinction and reinstatement of responding for alcohol. Doses of nicotine of 0.25, 1.25 and 7.5 mg/kg/24 h had no significant effects on the maintenance of responding for alcohol, but 5 mg/kg/24 h nicotine resulted in a significant increase in responding on the lever delivering the reward when water was substituted for the alcohol, indicating delayed extinction of responding. During infusion of 2.5 mg/kg/24 h nicotine, responding was significantly greater over the "sucrose-fading" training sessions, during acquisition of responding, when mixtures of alcohol and sucrose were provided as reward. When minipumps infusing 2.5 mg/kg/24 h nicotine were implanted after the alcohol responding had been acquired, the responding for alcohol increase during the first week of nicotine infusion, but corresponding nicotine infusion doses of 0.25, 1.25 and 7.5 had no significant effects. The results indicate that nicotine can increase operant responding for alcohol and this is crucially dependent on the dose of nicotine and the time of testing. The results have implications for the frequently encountered dependence on the combination of alcohol and nicotine.

Alcohol Drinking↗
PubMed2001

In vitro metabolism of chloroprene: species differences, epoxide stereochemistry and a de-chlorination pathway.

Chloroprene (1) was metabolized by liver microsomes from Sprague-Dawley rats, Fischer 344 rats, B6C3F1 mice, and humans to the monoepoxides, (1-chloro-ethenyl)oxirane (5a/5b), and 2-chloro-2-ethenyloxirane (4a/4b). The formation of 4a/4b was inferred from the identification of their degradation products. With male Sprague-Dawley and Fischer 344 rat liver microsomes, there was a ca. 3:2 preference for the formation of (R)-(1-chloroethenyl)oxirane (5a) compared to the (S)-enantiomer (5b). A smaller but distinct enantioselectivity in the formation of (S)-(1-chloro-ethenyl)oxirane occurred with liver microsomes from male mouse (R:S, 0.90:1) or male human (R:S, 0.86:1). 2-Chloro-2-ethenyloxirane was very unstable in the presence of the microsomal mixture and was rapidly converted to 1-hydroxybut-3-en-2-one (11) and 1-chlorobut-3-en-2-one (12). An additional rearrangement pathway of 2-chloro-2-ethenyloxirane gave rise to 2-chlorobut-3-en-1-al (14) and 2-chlorobut-2-en-1-al (15). Further reductive metabolism of these metabolites occurred to form 1-hydroxybutan-2-one (17) and 1-chlorobutan-2-one (18). In the absence of an epoxide hydrolase inhibitor, the microsomal incubations converted (1-chloroethenyl)oxirane to 3-chlorobut-3-ene-1,2-diol (21a/21b). When microsomal incubations were supplemented with glutathione, 1-hydroxybut-3-en-2-one was not detected because of its rapid conjugation with this thiol scavenger.

Animals↗
PubMed2001

Resolution of stroke deficits following contralateral grafts of conditionally immortal neuroepithelial stem cells.

BACKGROUND AND PURPOSE: Grafts of MHP36 cells have previously been shown to reduce dysfunction after global ischemia in rats. To test their efficacy after focal ischemia, MHP36 cells were grafted 2 to 3 weeks after transient intraluminal middle cerebral artery occlusion (tMCAO) in rats. METHODS: MHP36 cells were implanted into the hemisphere contralateral to the lesion, with 8 deposits of 3 microL of cell suspension (25 000 cells per microliter). Sham grafted rats received equivalent volumes of vehicle. Three groups, sham-operated controls (n=11), MCAO+sham grafts (n=10), and MCAO+MHP36 grafts (n=11), were compared in 3 behavioral tests. RESULTS: In the bilateral asymmetry test, MCAO+MHP36 grafted rats exhibited neglect before grafting but subsequently showed no significant dysfunction, whereas MCAO+sham grafted rats showed stable sensorimotor deficits over 18 weeks relative to controls. MCAO+sham grafted rats demonstrated spontaneous motor asymmetry and increased rotational bias after injection of dopamine agonists. MCAO+MHP36 and control groups exhibited no bias in either spontaneous or drug-induced rotation. In contrast to motor recovery, MCAO+MHP36 grafted rats showed no improvement relative to MCAO+sham grafted rats in spatial learning and memory in the water maze. MCAO produced large striatal and cortical cavitations in both occluded groups. Lesion volume was significantly reduced (P<0.05) in the MCAO+MHP36 grafted group. The majority of MHP36 cells were identified within the intact grafted hemisphere. However, MHP36 cells were also seen in the cortex, striatum, and corpus callosum of the lesioned hemisphere. CONCLUSIONS: MHP36 cells may improve functional outcome after MCAO by assisting spontaneous reorganization in both the damaged and intact hemispheres.

Amphetamine↗
PubMed2000

Functional reconstruction of the hippocampus: fetal versus conditionally immortal neuroepithelial stem cell grafts.

Late fetal CA1 hippocampal grafts and stem cell grafts from the conditionally immortal MHP36 clonal line derived from the H-2Kb-tsA58 transgenic mouse neuroepithelium both improved spatial deficits in rats with ischaemic CA1 damage induced by four-vessel occlusion (4VO). However, the distribution of fetal and MHP36 grafts differed. Fetal cells lodged in clumps around the implant sites and along the corpus callosum, whilst MHP36 grafts infiltrated the area of CA1 ischaemic damage, achieving apparent architectural reconstruction of the hippocampus. The migration of MHP36 cells is damage-dependent. Few cells were found in intact brain; after 15 min of 4VO cells repopulated only the discrete area of CA1 cell loss, whereas with more extensive damage after 30 min occlusion cells migrated to all hippocampal fields and to cortex. A higher proportion of grafted MHP36 cells differentiated into neurons in the host CA1 field than grafts of striatal or cortical expanded cell populations. Cortical population grafts were as effective as MHP36 grafts in improving water maze learning, whereas striatal or ventral mesencephalic cells were ineffective, indicating a degree of stem cell specificity. The efficacy of MHP36 cells extends to primates. In marmosets with profound impairments in conditional discrimination tasks after lesions of the CA1 field, MHP36 cells improved performance as effectively as fetal grafts and migrated evenly through the CA1 field, in contrast to clustered fetal cells. These findings suggest that MHP36 stem cell grafts are as effective as fetal grafts in functional repair of hippocampal damage, and that their preference for areas of cell loss and adoption of appropriate morphologies is consistent with a point-to-point repair mechanism.

Animals↗
PubMed2000

Investigations into pharmacological antagonism of general anaesthesia.

The effects of convulsant drugs, and of thyrotropin releasing hormone (TRH), were examined on the general anaesthetic actions of ketamine, ethanol, pentobarbitone and propofol in mice. The aim was to investigate the possibility of selective antagonism, which, if seen, would provide information about the mechanism of the anaesthesia. The general anaesthetic effects of ketamine were unaffected by bicuculline; antagonism was seen with 4-aminopyridine and significant potentiation with 300 mg kg(-1) NMDLA (N-methyl-DL-aspartate). The calcium agonist, Bay K 8644, potentiated the anaesthesia produced by ketamine and antagonism of such anaesthesia was seen with TRH. A small, but significant, antagonism of the general anaesthesia produced by ethanol was seen with bicuculline, and a small, significant, potentiation with 4-aminopyridine. There was an antagonist effect of TRH, but no effect of NMDLA. Potentiation of the anaesthetic effects of pentobarbitone was seen with NMDLA and with 4-aminopyridine and the lower dose of bicuculline (2.7 mg kg(-1)) also caused potentiation. There was no significant change in the ED(50) value for pentobarbitone anaesthesia with TRH. Bicuculline did not alter the anaesthetic actions of propofol, while potentiation was seen with NMDLA and 4-aminopyridine. TRH had no significant effect on propofol anaesthetic, but Bay K 8644 at 1 mg kg(-1) significantly potentiated the anaesthesia. These results suggest that potentiation of GABA(A) transmission or inhibition of NMDA receptor-mediated transmission do not appear to play a major role in the production of general anaesthesia by the agents used.

Anesthesia, General↗
PubMed2000

Metabolic inactivation of five glycidyl ethers in lung and liver of humans, rats and mice in vitro.

1. Some glycidyl ethers (GE) have been shown to be direct mutagens in short-term in vitro tests and consequently GE are considered to be potentially mutagenic in vivo. However, GE may be metabolically inactivated in the body by two different enzymatic routes: conjugation of the epoxide moiety with the endogenous tripeptide glutathione (GSH) catalysed by glutathione S-transferase (GST) or hydrolysis of the epoxide moiety catalysed by epoxide hydrolase (EH). 2. The metabolic inactivation of five different GE, the diglycidyl ethers of bisphenol A (BADGE), 4,4'-dihydroxy-3,3',5,5'-tetramethylbiphenyl (Epikote YX4000) and 1,6-hexanediol (HDDGE) and the GE of 1-dodecanol (C12GE) and o-cresol (o-CGE), has been studied in subcellular fractions of human, C3H mouse and F344 rat liver and lung. 3. All GE were chemically very stable and resistant to aqueous hydrolysis, but were rapidly hydrolysed by EH in cytosolic and microsomal fractions of liver and lung. The aromatic GE were very good substrates for EH. In general, microsomal EH is more efficient than cytosolic EH in hydrolysis of GE, and human microsomes are more efficient than rodent microsomes. 4. The more water-soluble GE, o-CGE and HDDGE, were good substrates for GST whereas the more lipophilic GE, YX4000 and C12GE, were poor substrates for GST. In general, rodents are more efficient in GSH conjugation of GE than humans. 5. In general, the epoxide groups of YX4000 are the most and those of HDDGE the least efficiently inactivated of the five GE under study. For the other three GE no general trend was observed: the relative efficiency of inactivation varied with organ and species. 6. The large variation in metabolism observed with five representative GE indicate that GE have variable individual properties and should not be considered as a single, homogenous class of compounds.

Adolescent↗
PubMed2000

Biomarkers of exposure to 1,3-butadiene as a basis for cancer risk assessment.

1,3-Butadiene (BD) is carcinogenic in mice and rats, with mice being considerably more sensitive than rats. Urine metabolites are 1, 2-dihydroxybutyl mercapturic acid (DHBMA) and a mixture of monohydroxy-3-butenyl mercapturic acids (MHBMA). The reactive metabolite 1,2-epoxy-3-butene forms 1- and 2-hydroxy-3-butenyl valine adducts in hemoglobin (MHBVal). The objectives of the study were (1) to compare the suitability of MHBMA, DHBMA, and MHBVal as biomarkers for low levels of exposure to BD, and (2) to explore relative pathways of metabolism of BD in humans for comparison with mice and rats, which is important in relation to cancer risk assessment in man. Analytical methods of measuring MHBMA, DHBMA, and MHBVal were modified and applied in 2 studies to workers engaged in the manufacture and use of BD. Airborne BD concentrations were assessed by personal air monitoring. MHBMA in urine was more sensitive for monitoring recent exposures to BD when compared to DHBMA and could measure 8-h time weighted average exposures as low as 0.13 ppm. Relatively high natural background levels in urine restricted the sensitivity of DHBMA. The origin of this background is currently unknown. The measurement of MHBVal adducts in hemoglobin was a sensitive method for monitoring cumulative exposures to BD at or above 0.35 ppm. Statistically significant relationships were found between urinary MHBMA and DHBMA concentrations, between either of these variables and 8-h airborne BD levels and between MHBVal adducts and average airborne BD levels over 60 days. The data on biomarkers demonstrated a much higher rate of hydrolytic metabolism of 1,2-epoxy-3-butene in humans compared to mice and rats, which was reflected in a much higher DHBMA/(DHBMA + MHBMA) ratio and in much lower levels of MHBVal in humans. Assuming a genotoxic mechanism, the data of this study, coupled with other published data on DNA and hemoglobin binding in mice and rats, suggest that the cancer risk for man from exposure to BD is expected to be less than for the rat and much less than for the mouse.

Acetylcysteine↗
PubMed2000

Quantification of DNA adducts formed in liver, lungs, and isolated lung cells of rats and mice exposed to (14)C-styrene by nose-only inhalation.

Bronchiolo-alveolar tumors were observed in mice exposed chronically to 160 ppm styrene, whereas no tumors were seen in rats up to concentrations of 1000 ppm. Clara cells, which are predominant in the bronchiolo-alveolar region in mouse lungs but less numerous in rat and human lung, contain various cytochrome P450s, which may oxidize styrene to the rodent carcinogen styrene-7,8-oxide (SO) and other reactive metabolites. Reactive metabolites may form specific DNA adducts and induce the tumors observed in mice. To determine DNA adducts in specific tissues and cell types, rats and mice were exposed to 160 ppm [ring-U-(14)C]styrene by nose-only inhalation for 6 h in a recirculating exposure system. Liver and lungs were isolated 0 and 42 h after exposure. Fractions enriched in Type II cells and Clara cells were isolated from rat and mouse lung, respectively. DNA adduct profiles differed quantitatively and qualitatively in liver, total lung, and enriched lung cell fractions. At 0 and 42 h after exposure, the two isomeric N:7-guanine adducts of SO (measured together, HPEG) were present in liver at 3.0 +/- 0.2 and 1.9 +/- 0.3 (rat) and 1.2 +/- 0.2 and 3.2 +/- 0.5 (mouse) per 10(8) bases. Several other, unidentified adducts were present at two to three times higher concentrations in mouse, but not in rat liver. In both rat and mouse lung, HPEG was the major adduct at approximately 1 per 10(8) bases at 0 h, and these levels halved at 42 h. In both rat Type II and non-Type II cells, HPEG was the major adduct and was about three times higher in Type II cells than in total lung. For mice, DNA adduct levels in Clara cells and non-Clara cells were similar to total lung. The hepatic covalent binding index (CBI) at 0 and 42 h was 0.19 +/- 0.06 and 0.14 +/- 0.03 (rat) and 0. 25 +/- 0.11 and 0.44 +/- 0.23 (mouse), respectively. The pulmonary CBIs, based on tissues combined for 0 and 42 h, were 0.17 +/- 0.04 (rat) and 0.24 +/- 0.04 (mouse). Compared with CBIs for other genotoxicants, these values indicate that styrene has only very weak adduct-forming potency. The overall results of this study indicate that DNA adduct formation does not play an important role in styrene tumorigenicity in chronically exposed mice.

Animals↗
PubMed1999

Effects of solvent on DNA adduct formation in skin and lung of CD1 mice exposed cutaneously to benzo(a)pyrene.

The effect of solvent polarity and lipophilicity on DNA adduct formation by polycyclic aromatic hydrocarbons in skin and lung has been studied in CD1 mice exposed cutaneously in vivo to benzo(a)pyrene ( approximately 0.01-7.0 microg/animal) in either tetrahydrofuran or n-dodecane. The nature and amounts of DNA adducts, measured as 7R,8S, 9R-trihydroxy-10S-(N(2)-deoxyguanosyl-3'-phosphate)-7,8,9, 10-tetrahydrobenzo(a)pyrene, in relation to exposure dose and treatment regime was determined by (32)P-postlabelling. In skin DNA there was a linear relationship between exposure dose and adduct formation with both solvents, though the amount of adduct formed was significantly lower from treatment with benzo(a)pyrene in n-dodecane than in tetrahydrofuran. The amounts of adducts measured in skin DNA ranged from 67 amol adducts/microg DNA at the lowest exposure dose of benzo(a)pyrene in n-dodecane to 3.5 fmol adducts/microg DNA (1 adduct in 5 x 10(7) nucleotides to 1 adduct in 9 x 10(5) nucleotides) at the highest dose. In tetrahydrofuran the corresponding levels were 89 amol adducts/microg DNA (1 adduct in 3 x 10(7) nucleotides) to 16.9 fmol adducts/microg DNA (1 adduct in 2 x 10(5) nucleotides). DNA adducts could not be detected in lung tissue following cutaneous treatment of animals with benzo(a)pyrene in n-dodecane. Cutaneous treatment of animals with benzo(a)pyrene in tetrahydrofuran, however, resulted in adducts in lung DNA at a level of 88 amol/microg DNA from exposures only at the highest dose (6.72 microg/animal). The difference in octanol-water partition coefficient, log P(ow) between n-dodecane compared to tetrahydrofuran is considered to be the most likely reason for the reduction in the bioavailability of benzo(a)pyrene and/or its metabolites and hence the degree of genotoxicity in tissues. The results suggest that other paraffinic hydrocarbon solvents may moderate the genotoxicity of polycyclic aromatic hydrocarbons in vivo. The assessment of the genotoxicity in vivo of mixtures of compounds should be carried out on complete mixtures of substances of interest in order to take account of these possible antagonistic or synergistic effects.

Administration, Topical↗
PubMed1999

Low alcohol preference among the "high alcohol preference" C57 strain of mice; preference increased by saline injections.

RATIONALE AND OBJECTIVE: This study investigated individual alcohol preference among the "high alcohol preferring" strain of C57BL10 (line ScSn) mice. METHODS: Alcohol preference was assessed in free choice two-bottle preference tests, using 8% ethanol and tap water, under various conditions. RESULTS: Between 15 and 40% of the mice, bred in house, showed a low preference for alcohol with ethanol/water ratios of 0.4 or less. There was a biphasic distribution of preference, and no relationship between alcohol preference and gender. Mice of the C57BL/6 strain from an outside breeder also contained animals with low preference for alcohol. Selective breeding from "in house" stock did not demonstrate evidence of a simple genetic link. Ethanol preference showed no correlation with locomotor activity or the effects of alcohol on such activity. Daily intraperitoneal injections of saline increased the preference of low preference mice, an effect prevented by the CCK(B) antagonist, CAM1028. The preference of "low preference" mice was significantly increased when the effects of saline injections were compared with those of handling alone. Diazepam, at 1 mg/kg, did not affect the low preference, compared with Tween vehicle. This demonstration of C57 strain mice with low preference for alcohol may provide a valuable model for the effects of stress on alcohol consumption.

Alcohol Drinking↗
PubMed1999

Prolonged effects of chronic ethanol treatment on responses to repeated nicotine administration: interactions with environmental cues.

The most common combination of dependence on two drugs occurs with alcohol and nicotine, but little is known of the way in which these drugs interact in the brain. This study investigated the effects in mice of prolonged consumption of alcohol, by liquid diet, on the actions of nicotine on locomotor activity, and the influence of environmental cues on these effects. Administration of nicotine after chronic alcohol intake did not show any significant changes on first administration, but after 28 days of daily nicotine injections, nicotine produced significant locomotor stimulation and increased rearing activity in the mice which had previously received the alcohol diet, compared with the activity of animals that received the control diet. However, significantly increased locomotor activity was also seen, after the repeated nicotine administration, immediately prior to the nicotine injection, only in the mice that had previously consumed alcohol. Examination of the influence of the environment in which the activity was tested demonstrated that the effect on activity prior to injections was seen only if measurement was made in a test environment that was familiar to the animals. The results demonstrate an interaction between chronic alcohol consumption and the effects of environment on the actions of nicotine, that may have relevance to the consumption of these drugs in humans.

Animals↗