ABSTRACT
We present results from the OP3 campaign in Sabah during 2008 that allow us to study the impact of local emission changes over Borneo on atmospheric composition at the regional and wider scale. OP3 constituent data provide an important constraint on model performance. Treatment of boundary layer processes is highlighted as an important area of model uncertainty. Model studies of land-use change confirm earlier work, indicating that further changes to intensive oil palm agriculture in South East Asia, and the tropics in general, could have important impacts on air quality, with the biggest factor being the concomitant changes in NO(x) emissions. With the model scenarios used here, local increases in ozone of around 50 per cent could occur. We also report measurements of short-lived brominated compounds around Sabah suggesting that oceanic (and, especially, coastal) emission sources dominate locally. The concentration of bromine in short-lived halocarbons measured at the surface during OP3 amounted to about 7 ppt, setting an upper limit on the amount of these species that can reach the lower stratosphere.
Subject(s)
Air Pollution/analysis , Arecaceae/chemistry , Atmosphere/chemistry , Trees/chemistry , Agriculture , Arecaceae/physiology , Atmosphere/analysis , Borneo , Bromine/chemistry , Butadienes/chemistry , Carbanilides/analysis , Carbanilides/chemistry , Computer Simulation , Formaldehyde/chemistry , Hemiterpenes/chemistry , Malaysia , Nitrogen Oxides/chemistry , Oxidation-Reduction , Ozone/chemistry , Pentanes/chemistry , Trees/physiology , Tropical Climate , Volatile Organic Compounds/chemistryABSTRACT
Replacement of the large hydantoin-indole moiety from our previous work with a variety of smaller heterocyclic analogues gave rise to potent CCR5 antagonists having binding affinity comparable to the hydantoin analogues. The synthesis, SAR, and biological profiles of this class of antagonists are described.
Subject(s)
Anti-HIV Agents/therapeutic use , CCR5 Receptor Antagonists , HIV Infections/drug therapy , Heterocyclic Compounds/therapeutic use , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , HIV-1/isolation & purification , HeLa Cells , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Structure-Activity RelationshipABSTRACT
A series of hydantoin derivatives has been discovered as highly potent nonpeptide antagonists for the human CCR5 receptor. The synthesis, SAR, and biological profiles of this class of antagonists are described.
Subject(s)
Anti-HIV Agents/therapeutic use , CCR5 Receptor Antagonists , HIV Infections/drug therapy , Hydantoins/therapeutic use , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , HIV-1/isolation & purification , Humans , Hydantoins/chemistry , Hydantoins/pharmacologyABSTRACT
Herein we report the preparation of a combinatorial library of compounds with potent CCR5 binding affinity. The library design was aided by SAR generated in a traditional medicinal chemistry effort. Compounds with novel combinations of subunits were discovered that have high binding affinity for the CCR5 receptor. A potent CCR5 antagonist from the library, compound 11 was found to have moderate anti-HIV-1 activity.
Subject(s)
CCR5 Receptor Antagonists , Combinatorial Chemistry Techniques , HIV-1/drug effects , Structure-Activity RelationshipABSTRACT
Investigations of the structure-activity relationships of 1,3,4-trisubstituted pyrrolidine human CCR5 receptor antagonists afforded orally bioavailable compounds with the ability to inhibit HIV replication in vitro.
Subject(s)
Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , HIV/drug effects , Pyrrolidines/pharmacology , Administration, Oral , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacokinetics , Biological Availability , CHO Cells , Cricetinae , HeLa Cells , Humans , Microbial Sensitivity Tests , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Structure-Activity RelationshipABSTRACT
(2S)-2-(3-Chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (1b) has been identified as a potent CCR5 antagonist having an IC50=10 nM. Herein, structure-activity relationship studies of non-spiro piperidines are described, which led to the discovery of 4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidine derivatives (3-5) as potent CCR5 antagonists.
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Butanes/chemistry , Butanes/chemical synthesis , Butanes/pharmacology , CCR5 Receptor Antagonists , Piperidines/chemistry , Piperidines/pharmacology , Animals , Cells, Cultured , Cricetinae , Drug Design , Drug Evaluation, Preclinical , HIV-1/drug effects , Humans , Inhibitory Concentration 50 , Neutrophils/drug effects , Neutrophils/virology , Structure-Activity RelationshipABSTRACT
Microbes whose genomes are encoded by DNA and for which adequate information is available display similar genomic mutation rates (average 0.0034 mutations per chromosome replication, range 0.0025 to 0.0046). However, this value currently is based on only a few well characterized microbes reproducing within a narrow range of environmental conditions. In particular, no genomic mutation rate has been determined either for a microbe whose natural growth conditions may extensively damage DNA or for any member of the archaea, a prokaryotic lineage deeply diverged from both bacteria and eukaryotes. Both of these conditions are met by the extreme thermoacidophile Sulfolobus acidocaldarius. We determined the genomic mutation rate for this species when growing at pH 3.5 and 75 degrees C based on the rate of forward mutation at the pyrE gene and the nucleotide changes identified in 101 independent mutants. The observed value of about 0.0018 extends the range of DNA-based microbes with rates close to the standard rate simultaneously to an archaeon and to an extremophile whose cytoplasmic pH and normal growth temperature greatly accelerate the spontaneous decomposition of DNA. The mutations include base pair substitutions (BPSs) and additions and deletions of various sizes, but the S. acidocaldarius spectrum differs from those of other DNA-based organisms in being relatively poor in BPSs. The paucity of BPSs cannot yet be explained by known properties of DNA replication or repair enzymes of Sulfolobus spp. It suggests, however, that molecular evolution per genome replication may proceed more slowly in S. acidocaldarius than in other DNA-based organisms examined to date.
Subject(s)
Genome, Archaeal , Sulfolobus acidocaldarius/genetics , Base Sequence , Molecular Sequence Data , MutationABSTRACT
Screening of the Merck sample collection for compounds with CCR5 receptor binding afforded (2S)-2-(3,4-dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (4) as a potent lead structure having an IC50 binding affinity of 35 nM. Herein, we describe the discovery of this lead structure and our initial structure activity relationship studies directed toward the requirement for and optimization of the 1-amino fragment.
Subject(s)
Anti-HIV Agents/chemical synthesis , CCR5 Receptor Antagonists , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/metabolism , CHO Cells , Chemokine CCL4 , Combinatorial Chemistry Techniques , Cricetinae , Humans , Inhibitory Concentration 50 , Macrophage Inflammatory Proteins/metabolism , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/metabolism , Protein Binding , Receptors, CCR5/genetics , Receptors, CCR5/metabolism , Structure-Activity Relationship , TransfectionABSTRACT
(2S)-2-(3,4-Dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (3) has been identified as a potent CCR5 antagonist lead structure having an IC50 = 35 nM. Herein, we describe the structure-activity relationship studies directed toward the requirement for and optimization of the C-2 phenyl fragment. The phenyl was found to be important for CCR5 antagonism and substitution was limited to small moieties at the 3-position (13 and 16: X= H, 3-F, 3-Cl, 3-Me).
Subject(s)
Anti-HIV Agents/chemical synthesis , CCR5 Receptor Antagonists , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/metabolism , Butanes/chemical synthesis , Butanes/chemistry , Butanes/metabolism , Butylamines/chemical synthesis , Butylamines/chemistry , Butylamines/metabolism , CHO Cells , Chemokine CCL4 , Combinatorial Chemistry Techniques , Cricetinae , Humans , Inhibitory Concentration 50 , Macrophage Inflammatory Proteins/metabolism , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/metabolism , Protein Binding , Receptors, CCR5/genetics , Receptors, CCR5/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/metabolism , TransfectionABSTRACT
The DNA polymerases (gp43s) of the related bacteriophages T4 and RB69 are B family (polymerase alpha class) enzymes that determine the fidelity of phage DNA replication. A T4 whose gene 43 has been mutationally inactivated can be replicated by a cognate RB69 gp43 encoded by a recombinant plasmid in T4-infected Escherichia coli. We used this phage-plasmid complementation assay to obtain rapid and sensitive measurements of the mutational specificities of mutator derivatives of the RB69 enzyme. RB69 gp43s lacking proofreading function (Exo(-) enzymes) and/or substituted with alanine, serine, or threonine at the conserved polymerase function residue Tyr(567) (Pol(Y567(A/S/T)) enzymes) were examined for their effects on the reversion of specific mutations in the T4 rII gene and on forward mutation in the T4 rI gene. The results reveal that Tyr(567) is a key determinant of the fidelity of base selection and that the Pol and Exo functions are strongly coupled in this B family enzyme. In vitro assays show that the Pol(Y567A) Exo(-) enzyme generates mispairs more frequently but extends them less efficiently than does a Pol(+) Exo(-) enzyme. Other replicative DNA polymerases may control fidelity by strategies similar to those used by RB69 gp43.
Subject(s)
Bacteriophages/enzymology , DNA Replication , DNA-Directed DNA Polymerase/metabolism , Alanine/chemistry , Alleles , Base Sequence , Cell Division , Chromatography, Gel , Cloning, Molecular , DNA-Directed DNA Polymerase/chemistry , Escherichia coli/metabolism , Genetic Complementation Test , Kinetics , Molecular Sequence Data , Mutagenesis , Mutation , Plasmids/metabolism , Sequence Homology, Nucleic Acid , Serine/chemistry , Threonine/chemistry , Thymidine/metabolism , Time Factors , Viral Proteins/metabolism , Viral Proteins/physiologyABSTRACT
This study was carried out to investigate the molecular basis for modulation of recombinant FMO3-catalyzed activity by the tricyclic antidepressants, imipramine and chlorpromazine. A mutant of human liver FMO3 (T428R) was formed by site-directed mutagenesis and characterized along with the native enzyme in order to elucidate a possible structure-function relationship. Functional properties of native and T428R human FMO3s were studied with methimazole as substrate. Both enzymes catalyzed the S-oxidation of methimazole with the same Km value. Imipramine modulated the activities of the native and T428R human FMO3s differently; the activity of the native FMO3 was increased at all concentrations, whereas the activity of the mutant enzyme was inhibited at concentrations above 300 microM. Chlorpromazine activated the native enzyme at all concentrations of methimazole but activated the mutant enzyme only at high substrate concentrations. The direction (activation or inhibition) and extend of modulation of FMO3 activity is not only dependent on the concentration of the modulator, it is also dependent on the substrate concentration. This study confirms our previous findings with FMO1 that position 428 is important in the interaction of the FMO with modulators.
Subject(s)
Arginine/genetics , Chlorpromazine/pharmacology , Imipramine/pharmacology , Mutagenesis, Site-Directed , Oxygenases/genetics , Oxygenases/metabolism , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Humans , Oxygenases/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
Human flavin-containing monooxygenase 3 (FMO3) is subject to modulation by tricyclic antidepressants and other agents. Imipramine activates FMO3-catalyzed metabolism of methimazole at all substrate concentrations tested. This distinguishes FMO3 from rabbit FMO1 and FMO2, which are activated at high substrate concentration and inhibited at low substrate concentration, and pig FMO1, which is inhibited at all substrate concentrations. The response of FMO3 is also unique in that chlorpromazine is markedly more effective as a modulator than is imipramine. n-Octylamine, MgCl2, and HgCl2 all inhibit FMO3, the first two in a biphasic manner. Substitution of lysine for threonine at position 428 significantly alters the response of FMO3 to modulators without changing the kinetic parameters for the metabolism of the substrate. Activation by imipramine and chlorpromazine is reduced or abolished and inhibition, most obvious at low substrate concentrations, is observed. This is consistent with elimination of self-activation in the metabolism of imipramine. The mutation at 428 also eliminates the biphasic nature of the inhibition by n-octylamine and MgCl2, but does not alter the effect of HgCl2. Our findings show that the activity of FMO3 can be modulated by large drug molecules as well as short-chain amines and metal ions. This modulation can be markedly altered by changing a single amino acid in the enzyme.
Subject(s)
Antidepressive Agents, Tricyclic/pharmacology , Oxygenases/metabolism , Amines/pharmacology , Amino Acid Substitution/genetics , Catalysis/drug effects , Chlorpromazine/metabolism , Chlorpromazine/pharmacology , Enzyme Activation/drug effects , Humans , Imipramine/metabolism , Imipramine/pharmacology , Lysine/genetics , Magnesium Chloride/pharmacology , Mercuric Chloride/pharmacology , Methimazole/metabolism , Mutagenesis, Site-Directed , Oxygenases/genetics , Threonine/geneticsABSTRACT
Variable amounts of flavin-containing monooxygenase isoforms 3 and 5 (FMO3 and FMO5) are present in microsomal preparations from adult, male, human liver. Quantitation with monospecific antibodies and recombinant isoforms as standards showed levels of FMO3 and of FMO5 that ranged from 12.5 to 117 and 3.5 to 34 pmol/mg microsomal protein, respectively. The concentration of FMO3 was greater than that of FMO5 in all samples, but the ratio of FMO3 to FMO5 varied from 2:1 to 10:1. Human hepatic microsomal samples also showed variable activities for the S-oxidation of methimazole. This activity was associated totally with FMO3; no participation of FMO5 was apparent. This conclusion was supported by several lines of evidence: first, the catalytic efficiency of FMO3 with methimazole was found to be approximately 5000 times greater than that of FMO5; second, the rate of metabolism showed a direct, quantitative relationship with FMO3 content; third, the plot of the relationship between metabolism and FMO3 content extrapolated close to the origin. A second reaction, the N-oxidation of ranitidine, exhibited a much higher Km with recombinant FMO3 than did methimazole (2 mM vs. 35 microM). However, a direct relationship between this reaction and FMO3 content in human hepatic microsomal preparations was also apparent. This result shows that even with a high Km substrate, FMO3-catalyzed metabolism can account for the majority of the product formation with some drugs. Our findings demonstrate that the contribution of FMO isoforms to human hepatic drug metabolism can be assessed quantitatively on the basis of the characteristics of the enzymes expressed in Escherichia coli.
Subject(s)
Isoenzymes/metabolism , Microsomes, Liver/enzymology , Oxygenases/metabolism , Adult , Antibodies/immunology , Antibody Specificity , Catalysis , Cimetidine/metabolism , Escherichia coli/enzymology , Histamine H2 Antagonists/metabolism , Humans , Kinetics , Male , RNA, Messenger/metabolism , Ranitidine/metabolism , Recombinant Proteins/metabolismABSTRACT
As a first step in understanding the regulation of the expression of flavin-containing monooxygenases (FMOs), we have isolated the FMO genes from the rabbit and characterized the gene for FMO1. Probes based on the 3', middle and 5' regions of the cDNAs encoding FMO1, FM02, FM03, and FM05 were generated by polymerase chain reaction. A mixture of the 5' probes was used to screen a genomic library, and isolated clones were identified by hybridization with individual 5' probes. The complete gene for FM01 was isolated as three overlapping clones and found to span approximately 40 kb. The gene contains eight introns, ranging in size from 1.4 to 10 kb and nine exons ranging in size from 73 to 747 bases. The gene for FMO1 seems to have multiple transcription start sites. A genomic clone containing a 5' segment of the FM02 gene was isolated and found to contain intron 1, exon 1, and part of intron 2. The first intron of FM02 is considerably smaller than that of FMO1 (0.3 vs. 3.8 kb), and its 3' junction is 52 bases to the 5' of the start codon, compared with 6 bases in the case of FM01. In contrast, the 5' junction of intron 2 is the same distance from the start codon in both genes. The 5'-flanking regions of the FMO1 and FM02 genes contain several putative glucocorticoid responsive elements.
Subject(s)
Isoenzymes/genetics , Oxygenases/genetics , Amino Acid Sequence , Animals , Base Sequence , Cloning, Molecular , DNA, Complementary , Exons , Genes , In Vitro Techniques , Introns , Male , Molecular Sequence Data , RNA, Messenger/biosynthesis , RNA, Messenger/isolation & purification , Rabbits , Transcription, GeneticABSTRACT
The inability to obtain flavin-containing monooxygenase 4 (FMO4) in heterologous systems has hampered efforts to characterize this isoform of the FMO gene family. Neither the human nor the rabbit ortholog of FMO4, each of which has been cloned and sequenced, has been expressed. Attempts to achieve expression of FMO4 have been made with Escherichia coli, baculovirus, yeast, and COS systems. The cDNAs encoding FMO4 have extended coding regions compared with those encoding other FMO isoforms. The derived amino acid sequences of FMO1, -2, -3, and -5 from all species examined contain about the same number of residues (531-535 residues), whereas the derived sequences of human and rabbit FMO4 contain 558 and 555 residues, respectively. We have investigated whether the elongation of the FMO4 coding region is related to the inability to achieve expression. The cDNA encoding human FMO4 has been modified by a single base change that introduces a stop codon at the consensus position. This modification allows for expression in E. coli. Lack of expression of intact FMO4 is caused by a problem that occurs following transcription, a problem that is overcome completely by relocation of the stop codon 81 bases to 5' of its normal position. Truncated FMO4 is expressed as an active enzyme with characteristics typical of an FMO isoform. Possible functional changes resulting from altering the 3'-end of an FMO were investigated with human FMO3. Elongation of the coding region of the FMO3 cDNA to the next available stop codon (FMO3*) resulted in the expression of an enzyme with properties very similar to those of unmodified FMO3. Elongation of FMO3 lowered the level of expression in E. coli but did not eliminate it. As with FMO4, the difference in expression levels between FMO3 and elongated FMO3 (FMO3*) appears to be related to translation rather than transcription. The functional characteristics of FMO3 and FMO3* are not significantly different.
Subject(s)
Oxygenases/genetics , Amino Acid Sequence , Base Sequence , Cloning, Molecular , DNA Primers/chemistry , Humans , Hydrogen-Ion Concentration , Methimazole/metabolism , Molecular Sequence Data , Oxygenases/metabolism , Recombinant Proteins/metabolism , Sequence Alignment , Sequence Homology, Amino Acid , Structure-Activity Relationship , Transcription, GeneticABSTRACT
The 25 April 1992 magnitude 7.1 Cape Mendocino thrust earthquake demonstrated that the North America-Gorda plate boundary is seismogenic and illustrated hazards that could result from much larger earthquakes forecast for the Cascadia region. The shock occurred just north of the Mendocino Triple Junction and caused strong ground motion and moderate damage in the immediate area. Rupture initiated onshore at a depth of 10.5 kilometers and propagated up-dip and seaward. Slip on steep faults in the Gorda plate generated two magnitude 6.6 aftershocks on 26 April. The main shock did not produce surface rupture on land but caused coastal uplift and a tsunami. The emerging picture of seismicity and faulting at the triple junction suggests that the region is likely to continue experiencing significant seismicity.
ABSTRACT
Induction of cytochrome P450 1A1 (P450 1A1) in a variety of tissues is a well established consequence of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Although localization of the induced protein within the lung has been described, the precise intracellular distribution of the enzyme is not clear. Analysis of tissue sections, microsomal proteins, and mRNA from lungs of treated and untreated rabbits established that P450 1A1 had been induced by treatment with TCDD. Rabbit lungs from animals treated with TCDD were examined with immunocytochemistry and in situ hybridization, to identify the cell types that contain P450 1A1 and those that contain mRNA encoding P450 1A1. Endothelial cells of the entire vascular bed of rabbit lung reacted markedly with anti-P450 1A1. Likewise, cells lining both arteries and veins, as well as capillary endothelial cells, reacted strongly with the cDNA probe for mRNA encoding P450 1A1. Clara cells at all levels of airway labeled prominently for both P-450 1A1 and P450 1A1 mRNA. In addition, type 2 cells, alveolar macrophages, and to a lesser degree, ciliated cells reacted with the cDNA probe. P450 reductase, which is required for P450 activity, has previously been identified in Clara cells, type 2 cells, and alveolar macrophages, but not in endothelium of rabbit lung. We have now obtained similar results for the localization of mRNA encoding P-450 reductase. This finding brings into question the function of P450 1A1 in endothelium.
Subject(s)
Cytochrome P-450 Enzyme System/biosynthesis , Lung/enzymology , NADPH-Ferrihemoprotein Reductase/biosynthesis , Polychlorinated Dibenzodioxins/pharmacology , Animals , Cytochrome P-450 Enzyme System/drug effects , Endothelium/cytology , Endothelium/drug effects , Endothelium/enzymology , Enzyme Induction , Immunohistochemistry , Lung/drug effects , Lung/ultrastructure , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/enzymology , Male , NADPH-Ferrihemoprotein Reductase/drug effects , Nucleic Acid Hybridization , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rabbits , Subcellular Fractions/enzymology , Tissue DistributionABSTRACT
Holocene deformation indicative of large subduction-zone earthquakes has occurred on two large thrust fault systems in the Humboldt Bay region of northern California. Displaced stratigraphic markers record three offsets of 5 to 7 meters each on the Little Salmon fault during the past 1700 years. Smaller and less frequent Holocene displacements have occurred in the Mad River fault zone. Elsewhere, as many as five episodes of sudden subsidence of marsh peats and fossil forests and uplift of marine terraces are recorded. Carbon-14 dates suggest that the faulting, subsidence, and uplift events were synchronous. Relations between magnitude and various fault-offset parameters indicate that earthquakes accompanying displacements on the Little Salmon fault had magnitudes of at least 7.6 to 7.8. More likely this faulting accompanied rupture of the boundary between the Gorda and North American plates, and magnitudes were about 8.4 or greater.
ABSTRACT
The presence of homologues of rabbit cytochrome P-450 isozyme 5 in pulmonary and hepatic microsomal preparations from guinea pig, mouse, monkey, hamster, and rat was examined by immunoblotting and inhibition of metabolism of 2-aminofluorene with antibodies to isozyme 5. Homologues to isozyme 5 were detected in pulmonary preparations from all five species. However, only hepatic preparations from hamster, in addition to those from rabbit, contained detectable levels of this isozyme. With the exception of induction by phenobarbital in rabbit liver, treatment of animals with phenobarbital or tetrachlorodibenzo-p-dioxin did not increase hepatic or pulmonary content of isozyme 5 homologues or the amount of 2-aminofluorene metabolism inhibited by antibodies to isozyme 5. Metabolism of 2-aminofluorene was measured both colorimetrically (formation of a reduced iron chelate from the N-hydroxyfluorene metabolite) and radiochemically (separation of 3H-metabolites by high performance liquid chromatography and quantitation by scintillation counting). A turnover number of 48 nmol of product X min-1 X nmol of enzyme-1 for isozyme 5-catalyzed metabolism of 2-aminofluorene was determined with incubations containing isozyme 5 purified from rabbit lung. A similar turnover number was calculated from the rabbit hepatic microsomal activity inhibited by antibodies to isozyme 5 and the microsomal isozyme 5 content measured by immunoquantitation. In other species, amounts of metabolism inhibited by antibodies to isozyme 5 agreed qualitatively with relative staining intensities on immunoblots. In all species except the hamster, rates of total and isozyme 5-catalyzed metabolism of 2-aminofluorene were greater with pulmonary than with hepatic microsomal preparations from untreated animals.
Subject(s)
Cytochrome P-450 Enzyme System/biosynthesis , Isoenzymes/biosynthesis , Lung/enzymology , Microsomes, Liver/enzymology , Microsomes/enzymology , Animals , Cricetinae , Enzyme Induction , Fluorenes/metabolism , Guinea Pigs , Lung/ultrastructure , Mesocricetus , Phenobarbital/pharmacology , Polychlorinated Dibenzodioxins/pharmacology , Rabbits , Rats , Species SpecificityABSTRACT
The placement success and quality of life of 69 mentally retarded persons placed into independent housing 5 years previously was evaluated. Eighty percent (n = 55) were still in their original independent housing placement. On the basis of multiple regression analysis, the most significant predictor variables were the behavioral skill areas of personal maintenance, communication, community integration, clothing care and use, and food preparation. Unsuccessful placements were related to bizarre behavior, nutritional problems, and inadequate home maintenance. Quality of life variables analyzed included employment, finances, community utilization, leisure-time usage, and friendship patterns. Analysis of the quality of life variables presented a mixed picture: Part of the data reflected low income and possible loneliness; on the other hand, community utilization occurred frequently and involved normal activities. Clients reported that they were proud of their apartments and felt good about "doing their own thing." In light of the results, an extended assistance-training model was presented.