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Biomedical subjects

A B Jones

Publications and source records attributed to A B Jones.

At least 55 records · Page 3Linked to original sources
PubMed1991

Rectal bioavailability of delta-9-tetrahydrocannabinol from the hemisuccinate ester in monkeys.

Oral administration of delta-9-tetrahydrocannabinal (delta 9-THC) was shown to result in low and erratic bioavailability, while the drug showed no bioavailability from various suppository formulations. delta 9-THC-Hemisuccinate was formulated as a prodrug for delta 9-THC in suppositories using Witepsol H15 base. The bioavailability of delta 9-THC from this formulation was evaluated in monkeys. The plasma levels of delta 9-THC and its metabolite 11-nor-delta 9-THC-9-COOH were determined using GC/MS analysis. The calculated bioavailability of delta 9-THC from this formulation was found to be 13.5%. Non-compartmental analysis of the plasma concentration data using statistical moments showed the mean residence time (MRT) for delta 9-THC in the body to be 3 h following iv administration of delta 9-THC or its hemisuccinate ester (3.4 and 2.7 h, respectively), as compared with 5.8 h following rectal administration of the delta 9-THC hemisuccinate. The observed rectal bioavailability of delta 9-THC from suppositories containing the hemisuccinate ester as a prodrug is of significant importance in developing an alternative approach to oral administration of the drug.

Administration, Rectal↗
PubMed1991

Distribution of cytochrome CYP2E1 in murine liver after ethanol and acetone administration.

The effects of acetone and ethanol administration on cytochrome CYP2E1 in murine liver were investigated. A monoclonal antibody (Mab 1-98-1) specific to rat ethanol-inducible P450 recognized a major band of Mr 51,000 in Western immunoblots of mouse liver microsomes. This band was increased 1.8-fold by 10% ethanol in drinking water for 2 weeks, 4.7-fold by 1% acetone in drinking water for 1 week, and 2.5-, 2.1- and 6.8-fold by ethanol in a liquid diet for 9 days, 2 weeks and 3 weeks respectively. Immunohistochemical staining experiments with the same antibody showed specific localization in centrilobular regions of liver lobules, with variations in intensity that corresponded to differences detected in Western immunoblots. Uniform cellular increases in centrilobular staining occurred with all ethanol treatments, whereas a more heterogeneous increase in individual cells was noted after acetone. Lipid accumulation in hepatocytes was pronounced after 3 weeks on the ethanol liquid diet but was less so in other treatment groups, and thus did not consistently correlate with enzyme induction. Microsomal aniline p-hydroxylase activity was also induced by the acetone and ethanol treatments, with a progressive increase from 9 days to 3 weeks on the ethanol liquid diet. Changes in this activity in general paralleled those found with immunohistochemistry and immunoblotting. The results demonstrate that (i) the mouse is a good model for correlative biochemical and histochemical studies of CYP2E1 induction, (ii) in the mouse liver, this P450 is preferentially localized in centrilobular regions constitutively as well as in induced states, (iii) the centrilobular pattern varies under different induction conditions, and (iv) there is a progressive inductive increase in CYP2E1 protein and enzyme activity with chronic ethanol treatment over at least 3 weeks.

Acetone↗
PubMed1991

Long-term (imprinting) effects of transplacental treatment of mice with 3-methylcholanthrene or beta-naphthoflavone on hepatic metabolism of 3-methylcholanthrene.

Foetal mice of genotype AhbAhd (responsive to induction of metabolism of polycyclic aromatic hydrocarbons [PAH]) or AhdAhd (non-responsive) were exposed transplacentally on gestation day 17 to a single dose of 3-methylcholanthrene (MC, 5-175 mg/kg) with or without prior treatment on day 15 with beta-naphthoflavone (beta NF, 150 mg/kg). The mothers were themselves either induction-responsive [(C57BL/6 x DBA/2)F1] or non-responsive (DBA/2). Metabolism of [14C]MC by homogenates of livers from the transplacentally-exposed offspring was quantified at 9 months of age (first experiment) or 13 months (second experiment) with or without prior inducing treatment with MC. The foetal exposure to MC had a permanent effect on MC metabolism by the adult hepatic homogenates in both experiments. In most instances the effect was positive in direction and small in magnitude (15-30%). It was dose-dependent with regard to transplacental MC, occurred in both induced (AhbAhd) and non-induced (AhdAhd) individuals, and was significant only when the mother and/or the foetus was inducible. beta NF itself did not have a positive imprinting effect. In some cases it either reduced or potentiated the long-term imprinting effect of MC, depending on the MC dose and the phenotype of the mother. These results confirm that transplacental exposure to a carcinogenic PAH may permanently alter metabolism of the chemical in later life, and indicate that this imprinting action is dependent on induced metabolism of the chemical in the mother and/or foetus.

Animals↗
PubMed1991

Coca paste: chemical analysis and smoking experiments.

Several samples of Colombian and a sample of Peruvian coca paste were subjected to chemical analysis to ascertain the complexity of these products. A neutral and acid fraction and a basic fraction were analyzed by gas chromatography/flame ionization detection (GC/FID) and gas chromatography/mass spectrometry (GC/MS). The basic fraction was also analyzed as its trimethylsilyl (TMS) derivative. Several gasoline residue components were identified in the neutral fraction. In addition to cocaine (greater than 60% in all cases), other alkaloids were identified. Lead and manganese analyses were carried out on these samples. While all the samples contained no lead (less than 45 ppm), most of the Colombian samples contained significant amounts of manganese (greater than 5%). Preliminary smoking experiments with a Colombian coca paste sample indicated that it behaves more like free cocaine than like a cocaine sulfate salt.

Alkaloids↗
PubMed1990

Effect of pretreatment with beta-naphthoflavone on tumorigenesis by N-nitrosoethylurea in five mouse strains.

The non-carcinogenic inducer of the Ah locus, beta-naphthoflavone (beta NF), was administered to females of 5 mouse strains at a dose of 150 mg/kg 48 h before treatment with a tumorigenic dose of the direct-acting carcinogen, N-nitrosoethylurea (ENU), once weekly for 4 weeks. The strains used were C57BL/6, C3H/He and NIH Swiss (responsive to Ah locus induction) and AKR and DBA/2 (induction-non-responsive). The ENU caused primary lung tumors in all strains and in some cases smaller numbers of other neoplasms, including lymphomas, sarcomas and hepatocellular tumors. The beta NF pretreatment did not reduce the numbers of any of the tumors, compared with mice given ENU alone. This result is in contrast to previous findings of a strong protective effect of beta NF against tumorigenesis in Ah-responsive strains by the metabolism-dependent carcinogens, benzo[a]pyrene and 3-methylcholanthrene and confirms that this protection is directly related to enzyme induction. beta NF treatment caused a significant doubling in the number of lung tumor bearers among the ENU-exposed C57BL/6 mice but in no other strain, suggesting the possibility of strain-specific tumor promotion.

Animals↗
PubMed1990

The formation of 3-methylcholanthrene-initiated lung tumors correlates with induction of cytochrome P450IA1 by the carcinogen in fetal but not adult mice.

The administration of 3-methylcholanthrene (MC) to pregnant mice results in the formation of lung tumors in the offspring. Previous work has shown that fetuses demonstrating inducibility of aryl hydrocarbon metabolism develop two to five times more lung tumors than induction-nonresponsive littermates. In this study, the effects of fetal versus adult MC exposure were compared with regard to both induction of aryl hydrocarbon hydroxylase activity (AHH) in lung and dependence of lung tumorigenesis on the Ah genotype. In inducible (C57BL/6 X DBA/2)F1 fetal lung supernatants, a single ip injection of 100 mg/kg of MC to the mothers resulted in a maximal 50-fold induction of AHH activity by 8 hr, which persisted for 48 hr. The enzyme data agreed well with RNA blot analysis, as MC caused maximal induction of P450IA1 RNA by 4 hr. For comparison, adult (F1 X DBA/2) mice were given three weekly injections of 100 mg/kg MC and tumor incidences were determined after 16 weeks. No differences were observed between responsive and nonresponsive mice of either sex in the number of mice bearing lung tumors, nor did the tumor multiplicity differ between responsive and nonresponsive males. However, noninducible female mice had a significantly higher tumor multiplicity than their inducible counterparts (p less than 0.025). Single ip injections of MC to adult F1 mice revealed that lung AHH activity was increased only 4- to 7-fold in the adult animal compared to the large fetal induction ratio. The difference in the magnitude of induction was due to the higher constitutive levels of AHH activity seen in adult tissue (4- to 14-fold greater than maximal basal fetal levels), as fetal and adult supernatants showed similar levels of induced activity following MC treatment. These results suggest that the correlation between susceptibility to MC-initiated lung tumors and induction of cytochrome P450IA1 is a unique property of the fetus and may be due, in part, to the low basal levels of fetal activating enzymes and their high induction ratio during the fetal period.

Animals↗
PubMed1990

Role of the maternal environment in determining susceptibility to transplacentally induced chemical carcinogenesis in mouse fetuses.

Treatment of pregnant mice with 3-methylcholanthrene (MC) causes lung and liver tumors in the offspring, the incidences of which are greatly influenced by the Ah locus regulated induction phenotype for aryl hydrocarbon hydroxylase activity (AHH) in both the mother and fetuses. In order to examine the biochemical and molecular mechanisms responsible for the modulating effect of maternal environment on tumor susceptibility, reciprocal crosses between responsive C57BL/6 and non-responsive DBA/2 mice were made and the pregnant mothers were treated i.p. on the 17th day of gestation with either olive oil alone, 30 mg/kg of MC, or 30 mg/kg of beta-naphthoflavone (beta NF). At various times after injection, the mothers were killed and the fetuses removed for enzymatic and molecular blot analysis. In fetal lung tissues, the absolute levels and relative induction ratios of AHH activity from D2B6F1 fetuses were very similar to those obtained in B6D2F1 fetuses during the first 24 h following a transplacental exposure to either inducing agent. This was also the case 48 h after an injection of beta NF. However, 48 h after exposure to MC, the AHH activity in fetal lungs from B6 mothers had declined to practically control values, whereas fetal lungs from D2 mothers still exhibited a high level of AHH activity. Similar induction kinetics for the CYPIA1 gene were obtained in fetal livers. These results were confirmed at the RNA level by quantitative slot-blot analysis of fetal RNA preparations. In both organs, treatment with inducing agents for the P450IA1 gene resulted in a rapid and early induction of CYPIA1 RNA by 4 h. Fetuses from D2 mothers, however, showed a more sustained induction of CYPIA1 RNA following exposure to MC than did fetuses from B6 mothers. These results suggest that the observed increase in tumor susceptibility observed in the offspring of D2 mothers compared to the offspring of B6 mothers was due, at least in part, to the differences in the persistence of induction of the CYPIA1 gene locus, and may be the result of differences in the clearance rates of MC from the fetal and maternal compartments or its pharmacokinetic distribution in the two types of maternal environments.

Animals↗
PubMed1990

Renal function during onset of carbachol-induced hypertension in conscious rats.

This study evaluated the changes in renal function that occur during the early phases of chronic infusion of carbachol into the lateral ventricle in conscious rats. Infusion of 1.0 micrograms/h of carbachol i.c.v. resulted in a prompt pressor response with mean arterial pressure rising 20 mm Hg within 15 min. The pressure remained elevated for the duration of a 2-hour infusion. Carbachol infusion at 0.5 micrograms/h induced a similar elevation in blood pressure, but the onset was delayed, reaching significance only after 30-60 min. The higher dose of carbachol was associated with a marked and sustained natriuresis, with sodium excretion increasing from 2.1 +/- 0.3 to 5.3 +/- 1.0 microEq/100 g min after 2 h, compared to 2.0 +/- 0.5 and 1.8 +/- 0.3 microEq/100 g min in vehicle-infused control animals. Sodium excretion did not change significantly in animals infused with carbachol at 0.5 microgram/h. There were no significant changes in glomerular filtration rate in any of the groups. Plasma levels of atrial natriuretic peptide (ANP) were not altered significantly by ventricular infusion of carbachol (188 +/- 99 before vs. 83 +/- 17 pg/ml after infusion). It is concluded that the pressor response to central carbachol infusion is not dependent on retention of sodium and water. The natriuresis observed with carbachol infusion can be dissociated from the pressor response, and is not mediated by ANP.

Animals↗
PubMed1989

Modification of transplacental tumorigenesis by 3-methylcholanthrene in mice by genotype at the Ah locus and pretreatment with beta-naphthoflavone.

Transplacental lung and liver tumorigenesis in the mouse by 3-methylcholanthrene (MC) was assessed as a function of inducibility of MC metabolism in fetus and in mother, and of pretreatment of the mothers with a noncarcinogenic inducer, beta-naphthoflavone (beta NF). Pregnant (C57BL/6 X DBA/2)F1 females (genotype Ahb Ahd, inducer responsive) mated to DBA/2 males received 45 or 100 mg/kg MC on gestation day 17, and DBA/2 females (genotype Ahd Ahd, nonresponsive) mated to F1 males were given 5 or 30 mg MC/kg. These crosses generated both responsive and nonresponsive offspring. Phenotype and tumor incidences were determined at 13 months of age. The transplacental action of MC was dose dependent and resulted in more lung and liver tumors in induction-responsive offspring than in nonresponsive littermates in most comparisons. beta NF alone did not result in increased numbers of tumors. Significant, complex effects were seen when the mothers were pretreated with beta NF (150 mg/kg) on gestation day 15, before MC on day 17. The beta NF pretreatment protected the fetuses of the F1 mothers: there was a significant overall 30 to 50% reduction in numbers of lung and liver tumors. The greatest effect was seen in the induction-responsive males, who experienced a 50% reduction in both incidence and multiplicity of lung tumors after 100 mg MC/kg, compared with males exposed to MC only. By contrast, beta NF pretreatment of DBA mothers had no general effect but rather potentiated the action of the 5 mg MC/kg dose on multiplicity of lung tumors in inducible males, causing a significant 4-fold increase. It also caused a 60% increase in inducible male liver tumor multiplicity when given before the 30 mg MC/kg dose. Thus, beta NF pretreatment was protective when the mother was inducible, especially in the inducible fetuses of such a mother, but when the mother was noninducible the beta NF pretreatment had no effect in some situations and potentiated the action of the carcinogen in others, mainly in inducible fetuses. These results underscore the fact that induced maternal and fetal metabolism contribute to risk of transplacental tumorigenesis by MC in qualitatively opposite ways.

Animals↗
PubMed1989

Differential induction of fetal mouse liver and lung cytochromes P-450 by beta-naphthoflavone and 3-methylcholanthrene.

Previous studies have shown that the incidences of liver and lung tumors in mice exposed transplacentally to 3-methyl-cholanthrene (MC) were significantly influenced by the sensitivity of both mothers and fetuses to induction of cytochrome(s) P-450 by polycyclic aromatic hydrocarbons. In order to delineate further the biochemical and molecular processes underlying the observed biological effects, the inductive effect of MC and beta-naphthoflavone (beta NF) on cytochrome P-450 was determined at the biochemical and molecular levels. C57BL/6 females were mated with DBA/2 males and treated i.p. on day 17 of gestation with olive oil alone, 150 mg/kg of beta NF or different doses of MC. At various times after injection the mothers were sacrificed and the fetuses removed for biochemical and molecular studies. MC caused maximal induction of aryl hydrocarbon hydroxylase (AHH) activity by 8 h in both the liver and lung. beta NF caused nearly maximal induction of AHH activity by 8 h in the lung but had little effect on liver AHH activity at this time. Maximal induction with beta NF occurred by 24 h in both organs. Addition of monoclonal antibody 1-7-1, specific for the MC-inducible forms of cytochrome P-450 (P-450IA1 and A2), to the incubation mixtures resulted in a 55-70% inhibition of AHH activity in both lung and liver assays, regardless of the inducing agent used, while having no effect on AHH activity from oil-treated mice. RNA blot analysis carried out in parallel with enzyme assays demonstrated that the levels of enzyme activity correlated very well with the levels of steady-state RNAs. MC caused maximal induction of P-450IA1 RNA levels 4 h after injection in both organs and a biphasic secondary increase was observed in the lung. Maximal levels of P-450IA1 RNA were seen at 12-16 h following injection of beta NF. However, the ratio of P-450IA1 RNAs present at 16 versus 2 h in the beta NF-treated liver appeared greater than that in the lung. P-450IA2 was also induced in fetal liver and lung, but at low levels relative to P-450IA1. The results indicate that the increase in functional AHH activity was primarily due to induction of cytochrome P-450IA1. The differences in induction kinetics observed for cytochromes P-450IA1 and A2 suggest that these enzymes exhibit both tissue- and inducer-dependent specificity.

Animals↗
PubMed1989

Metabolism of transplacental carcinogens.

Literature on fetal metabolism of carcinogens since 1980 has been systematically listed and selectively discussed. The published data continues to support the conclusion that animal and human fetal tissues have the capacity to metabolize carcinogens, but at a low rate compared to the adult. Metabolism of low-molecular-weight chemicals, including nitrosamines, appears only near term in the rodent and is poorly inducible transplacentally; these agents are correspondingly relatively ineffective as fetal carcinogens. Metabolism of aromatic carcinogens, by contrast, appears early in gestation and is highly inducible transplacentally in rodents by chemicals such as polycyclic aromatic hydrocarbons (PAH) and tetrachlorodibenzo-p-dioxin, resulting in dramatic percent increases in enzyme activity. Transplacental induction has not been unequivocally demonstrated for the human fetus. Phase II enzymes, metabolizing aromatic compounds to water-soluble forms, generally have higher constitutive activity but lower degree of inducibility in the fetus, compared with phase I (activating) enzymes, and appear to show quantitatively different patterns in the human compared with the rodent. Specific and sensitive new technologies, including 32P-postlabelling, immunodetection of specific proteins, and use of cDNA probes, are beginning to be applied to fetal systems and are providing a more definitive and detailed understanding of the ontogeny and modulation of fetal carcinogen metabolizing enzymes. Fetal and maternal metabolism of PAH, especially methylcholanthrene (MC), have been found to be important determinants in susceptibility of the fetus to tumorigenesis. In particular, we have utilized a mouse model system wherein a single dominant gene, Ah, confers responsiveness to induction of PAH metabolism by cytochrome Pl450 (IA1); the recessive allele, Ah, is associated with nonresponsiveness. In appropriate backcrosses between C57BL/6 (AhAh) and DBA/2 (AhAh) mice, responsive and nonresponsive fetuses were carried together in mothers who were, themselves, either responsive or nonresponsive. In both cases, responsive fetuses later developed more lung and liver tumours after transplacental MC, compared with nonresponsive littermates. Fetuses of responsive mothers, however, experienced a lower cancer risk than did those of nonresponsive mothers at a comparable MC dose. Pretreatment of the pregnant mice with the noncarcinogenic inducer, beta-naphthoflavone (BNF) had a uniform protective effect for all of the fetuses, especially the responsive ones, if the mother was responsive. For nonresponsive mothers, by contrast, BNF pretreatment led to an enhancement of tumorigenesis, in the responsive fetuses only, under certain conditions of dose and fetal sex.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Gas chromatographic/mass spectrometric analysis of morphine and codeine in human urine of poppy seed eaters.

In this study, poppy seeds were examined for a natural constituent that might serve as a maker for the seeds' ingestion as opposed to opiate abuse. Thebaine was selected as possible marker, since it was found to be a component of all poppy seeds examined and was not a natural component of different heroin samples. During the course of this investigation, a new extraction and cleanup procedure was developed for the gas chromatographic/nitrogen phosphorus detection (GC/NPD) and gas chromatographic/mass spectrometric (GC/MS) analysis of morphine and codeine in urine. A linear response, over a concentration range of 25 to 600 ng/mL, was obtained for codeine and morphine (r = 0.9982 and 0.9947, respectively). The minimum detectable level (LOD) and limit of quantitation (LOQ) for morphine were 10 and 30 ng/mL, respectively; whereas LOD and LOQ for codeine were 2 and 8 ng/mL, respectively. The coefficients of variance (CV, n = 6) for morphine and codeine analyses at the 100-ng/mL level were 13.3 and 4.6%, respectively. This procedure was used for the analysis of urine samples from five poppy seed eaters who each ingested 200 g of poppy seed cake. Results indicated that significant amounts of morphine and codeine are excreted in urine and that in all subjects, at least at one point in time, the apparent morphine concentration as determined by radioimmunoassay (RIA) analysis exceeded the cutoff value (300 ng/mL) established for screening. Thebaine was not detected in urine specimens collected following poppy seeds ingestion and thus could not be used as a marker.

Chromatography, Gas↗
PubMed1987

Immunohistochemical determination of inducibility phenotype with a monoclonal antibody to a methylcholanthrene-inducible isozyme of cytochrome P-450.

A monoclonal antibody (MAb) to a methylcholanthrene (MC)-induced cytochrome P-450, designated MAb 1-7-1, was used for immunohistochemical staining of formalin-fixed tissues from oil- and MC-treated C57BL/6, DBA/2, and [(C57BL/6 X DBA/2) F1 X DBA/2] F2 mice. An avidin-biotin-peroxidase complex immunohistochemical technique was used. For controls, the tissues were also exposed to MAbs 1-48-5 and HyHel-9 (to egg white lysozyme). In liver, MAb 1-7-1 specifically stained the cytoplasm of centrilobular hepatocytes of C57BL/6 mice treated with MC (80 mg/kg) 48 h before kill; staining was not observed with vehicle-treated C57BL/6 mice, with oil- or MC-treated DBA/2 mice, or with comparable antibody concentrations of control MAbs 1-48-5 or HyHel-9. In the F2 mice, about 50% were expected to be MC inducible (AhbAhd). Inducibility phenotype was determined by measuring the conversion of [14C]MC to oxidized and conjugated products by liver homogenates. In freshly fixed material from MC-treated mice, those livers shown by the determination of phenotype to be inducible also stained with MAb 1-7-1, whereas those not induced were immunohistochemically negative. Furthermore, there was a significant positive correlation between degree of staining and the level of MC-metabolizing activity measured biochemically. The immunohistochemical procedure was also accurate in determination of inducibility phenotype of livers that had been in paraffin blocks for up to 2 yr if more concentrated antibody was used. In lung, MAb 1-7-1 stained specifically the alveolar walls and endothelium of blood vessels in MC-induced C57BL/6 mice only; the control MAbs and other mice gave negative results. Similarly, in kidney MAb 1-7-1 stained only glomeruli and interstitial tissue of MC-induced C57BL/6 mice and only endothelium of blood vessels in the colons of these mice. These observations are consistent with induction of the cytochrome P-450 recognized by MAb 1-7-1 in the endothelial cells of extrahepatic tissue. Immunohistochemical staining with MAb thus shows great promise for highly specific localization of particular species of cytochromes P-450 in tissues, for in situ quantification of these enzymes, and for determination of inducibility phenotype with fixed material.

Animals↗
PubMed1987

Comparison of serum progesterone levels in dogs after administration of progesterone by vaginal tablet and vaginal suppositories.

Serum progesterone levels from a vaginal tablet formulation and six different vaginal suppository formulations, each containing 25 mg of progesterone, were evaluated in mongrel dogs. Bioavailabilities relative to an intravenous dose of progesterone were calculated. The vaginal tablet was found to have a significantly higher bioavailability compared with the vaginal suppositories.

Administration, Intravaginal↗