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Biomedical subjects

J D McKinney

Publications and source records attributed to J D McKinney.

At least 37 records · Page 2Linked to original sources
PubMed1994

Polychlorinated biphenyls as hormonally active structural analogues.

Among the environmental chemicals that may be able to disrupt the endocrine systems of animals and humans, the polychlorinated biphenyls (PCBs) are a chemical class of considerable concern. One possible mechanism by which PCBs may interfere with endocrine function is their ability to mimic natural hormones. These actions reflect a close relationship between the physicochemical properties encoded in the PCB molecular structure and the responses they evoke in biological systems. These physicochemical properties determine the molecular reactivities of PCBs and are responsible for their recognition at biological acceptors and receptors, as well as for triggering molecular mechanisms that lead to tissue response. "Coplanarity" of PCB phenyl rings and "laterality" of chlorine atoms are important structural features determining specific binding behavior with proteins and certain toxic responses in biological systems. We compare qualitative structure-activity relationships for PCBs with the limited information on the related non-coplanar chlorinated diphenyl ethers, providing further insights into the nature of the molecular recognition processes and support for the structural relationship of PCBs to thyroid hormones. Steroidlike activity requires conformational restriction and possibly hydroxylation. We offer some simple molecular recognition models to account for the importance of these different structural features in the structure-activity relationships that permit one to express PCB reactivities in terms of dioxin, thyroxine, and estradiol equivalents. The available data support the involvement of PCBs as mimics of thyroid and other steroidal hormones. The potential for reproductive and developmental toxicity associated with human exposure to PCBs is of particular concern.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Negative regulation of FAR1 at the Start of the yeast cell cycle.

In budding yeast, a switch between the mutually exclusive pathways of cell cycle progression and conjugation is controlled at Start in late G1 phase. Mating pheromones promote conjugation by arresting cells in G1 phase before Start. Pheromone-induced cell cycle arrest requires a functional FAR1 gene. We have found that FAR1 transcription and protein accumulation are regulated independently during the cell cycle. FAR1 RNA and protein are highly expressed in early G1, but decline sharply at Start. Far1 is phosphorylated just before it disappears at Start, suggesting that modification may target Far1 for degradation. Although FAR1 mRNA levels rise again during late S or G2 phase, reaccumulation of Far1 protein to functional levels is restricted until after nuclear division.

Base Sequence↗
PubMed1992

Comparative molecular field analysis of polyhalogenated dibenzo-p-dioxins, dibenzofurans, and biphenyls.

Comparative molecular field analysis (CoMFA) was performed on polyhalogenated dibenzo-p-dioxins, dibenzofurans, and biphenyls for Ah (dioxin) receptor binding and associated enzyme inducing activities determined by others using in vitro assays. Since various members of all three classes of compounds have been shown to produce qualitatively similar toxicities, a separate CoMFA was performed on each class of compounds and combinations of the different classes for each bioactivity which included combining all three classes of molecules in one CoMFA study. For the Ah receptor binding, the CoMFA-derived QSARs for all three classes of compounds and combinations thereof showed strong crossvalidated correlations indicating that they are highly predictive. For enzyme induction, the CoMFA-derived QSARs were highly predictive for the dibenzofurans but were only partially successful for the dioxins. For the biphenyls, the results were clearly unpredictive. The overall results of these CoMFA studies which include both steric and electrostatic considerations are compared and contrasted to other SAR models that have met with some success in making qualitative predictions about the potential for receptor binding and associated toxicity in these classes of compounds. The CoMFA-derived QSAR for the dioxin series of molecules in most cases significantly overestimates the enzyme inducing ability of the ortho-substituted biphenyls. This weak inducing activity of the o-biphenyls is, however, consistent with their relatively low dioxin-like toxicity as measured in other biological systems. Fundamentally different mechanisms may be operating in the expression of dioxin-like toxic responses for the o-biphenyls, and their direct, dioxin-like toxic equivalency perhaps needs to be reconsidered in this light.

Aryl Hydrocarbon Hydroxylases↗
PubMed1991

Transcriptional regulation in the eukaryotic cell cycle.

Cell-cycle-regulated transcription is a characteristic feature of complex cell cycles in organisms as divergent as yeasts and humans. Increasing evidence suggests that transcriptional regulation may control key events in the eukaryotic cell cycle. In this review we will address the mechanisms that may regulate transcription during the cell cycle and the roles which periodic transcription may serve in the control of cell cycle progression.

Cell Cycle↗
PubMed1990

Disease-causing effects of environmental chemicals.

Both toxicologic studies and studies in environmental chemistry are important in assessing the potential adverse health effects of human exposures to hazardous environmental agents. This article discusses the toxic effects of chemical concentration at the target organ or site and how the concentration is related to the level of external exposure.

Dose-Response Relationship, Drug↗
PubMed1989

Expression of cloned rpoB gene of Escherichia coli: a genetic system for the isolation of dominant negative mutations and overproduction of defective beta subunit of RNA polymerase.

The rifampin resistance rifD18 allele of rpoB, carried on the expression plasmid pXT7 beta, is controlled by a strong bacteriophage T7 late promoter and two weak Escherichia coli promoters. Depending on the host strain, pXT7 beta specifies different levels of Rifr beta subunit, providing a system for the isolation, maintenance, and overexpression of dominant lethal alleles of rpoB. In rpoB+ hosts, pXT7 beta confers the Rifr phenotype on the Rifs host. Negative rpoB mutations in the plasmid DNA can thus be scored by screening transformants for Rifs. In an rpoB(Am) supD(Ts) host in which chromosomal rpoB expression is decreased as the temperature goes up, some of the negative plasmid-borne rpoB mutations displayed a dominant phenotype. In a host harboring inducible T7 RNA polymerase, the defective beta subunits could be overexpressed independently of the E. coli transcriptional machinery. With this system, we isolated several negative rpoB mutations induced in vitro by hydroxylamine. Seven of the mutant rpoB alleles, when overexpressed, were found to specify normal-size beta polypeptides. Two of them displayed the dominant lethal phenotype in the rpoB(Am) supD(Ts) background. We also constructed a mutation (rpoB1800) in which 24 carboxy-terminal amino acids were substituted with a random 19-amino-acid sequence. The nonfunctional rpoB1800 beta polypeptide was isolated and assembled in vitro into the core enzyme molecule.

Cloning, Molecular↗
PubMed1989

Longitudinal research on the behavioral characteristics of children with learning disabilities.

This paper summarizes a program of research on the behavioral characteristics of children with learning disabilities (LD) compared to average achievers. Longitudinal studies over a 3-year period beginning in the first and second grades showed that children with LD, as a heterogeneous group, displayed a persistent pattern of maladaptive classroom behavior that distinguished them from average achieving peers and that was associated with continued underachievement over time. Subsequently, children with LD in the longitudinal sample were clustered into seven different subtypes that represented attention problems, conduct and classroom management problems, withdrawn-dependent behavior, and normal behavior. Although no differences in achievement were found initially between behavioral subtypes, children in the attention and conduct problem subtypes had poorer academic outcomes 3 years later compared to those in the withdrawn subtype and those who had no significant behavior problems. The collective findings from this research are discussed in terms of the developmental relationship between learning disabilities, attention disorders, and social/emotional problems, and implications are drawn for a greater focus on behavioral interventions in special education and prevention efforts in the early grades.

Adjustment Disorders↗
PubMed1989

Multifunctional receptor model for dioxin and related compound toxic action: possible thyroid hormone-responsive effector-linked site.

Molecular/theoretical modeling studies have revealed that thyroid hormones and toxic chlorinated aromatic hydrocarbons of environmental significance (for which dioxin or TCDD is the prototype) have similar structural properties that could be important in molecular recognition in biochemical systems. These molecular properties include a somewhat rigid, sterically accessible and polarizable aromatic ring and size-limited, hydrophobic lateral substituents, usually contained in opposite adjoining rings of a diphenyl compound. These molecular properties define the primary binding groups thought to be important in molecular recognition of both types of structures in biochemical systems. Similar molecular reactivities are supported by the demonstration of effective specific binding of thyroid hormones and chlorinated aromatic hydrocarbons with four different proteins, enzymes, or receptor preparations that are known or suspected to be involved in the expression of thyroid hormone activity. These binding interactions represent both aromatic-aromatic (stacking) and molecular cleft-type recognition processes. A multiple protein or multifunctional receptor-ligand binding mechanism model is proposed as a way of visualizing the details and possible role of both the stacking and cleft type molecular recognition factors in the expression of biological activity. The model suggests a means by which hormone-responsive effector-linked sites (possible protein-protein-DNA complexes) can maintain highly structurally specific control of hormone action. Finally, the model also provides a theoretical basis for the design and conduct of further biological experimentation on the molecular mechanism(s) of action of toxic chlorinated aromatic hydrocarbons and thyroid hormones.

Animals↗
PubMed1989

Polybrominated naphthalene and diiodobenzene interactions with specific binding sites for 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat liver cytosol.

We provide evidence for two new classes of halogenated aromatic hydrocarbon ligands for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or Ah) receptor: brominated naphthalenes and iodobenzenes. Polybrominated naphthalenes with four or more bromine atoms concentrated in lateral positions were shown to bind specifically and with high affinity (Kd approximately 10(-8) M) to the Ah receptor in rat liver cytosol preparations. The hexabrominated naphthalene isomers bind with high and nearly equal affinities but have been previously shown to have different toxicological properties. Possible explanations for these differences include differences in metabolism, antagonist versus agonist Ah receptor binding of some isomers, and the involvement of other binding sites in vivo that require different structural requirements. The moderate binding activity of the diiodobenzenes suggests that thyroid hormones should receive further study as possible endogenous ligands for the Ah receptor. It is difficult to explain the binding results with these two classes of compounds using previously developed molecular concepts for Ah receptor interactions based primarily on molecular size considerations.

Animals↗
PubMed1988

Molecular complexes of thyroid hormone tyrosyl rings with aromatic donors. Possible relationship to receptor protein interactions.

Several lines of evidence have indicated that thyroid hormones share common molecular properties (accessible planar face and lateral halogenation) with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds of environmental importance and can modulate their toxicity. Binding of dioxin to a soluble intracellular protein (dioxin or Ah receptor) appears to be the initial step in their mechanism of toxicity and a stacking interaction model has been proposed at the molecular level. It has also been recognized that the Ah receptor and the triiodothyronine nuclear receptor share certain physical and chemical properties important in their binding interactions. In this work, we examined the possibility that thyroid hormones might also be able to bind by a stacking complexation mechanism. By use of methods based on nuclear magnetic resonance spectroscopy, selected, structurally distinct thyroid hormone analogues with widely different hormonal activities were shown to function as electron acceptors in molecular complexes with aromatic donors involving the nonphenolic or tyrosyl ring. Binding free energies for these complexes correlated well with those previously reported for the triiodothyronine (L-T3) nuclear receptor binding interaction with the same compounds. This included preference for L-T3 over thyroxine (L-T4), very favorable binding of 3,5,3'-triiodothyroacetic acid (Triac), and marked preference for L-T3 over D-T3. These results suggest that a considerable part of the structural specificity in thyroid hormone action may be mediated by the tyrosyl ring interaction. Binding ligands for the triiodothyronine nuclear receptor and the Ah receptor may share common molecular parameters in the expression of their binding activities.

Magnetic Resonance Spectroscopy↗
PubMed1988

Estrogen receptor-binding activity of polychlorinated hydroxybiphenyls: conformationally restricted structural probes.

A series of polychlorinated hydroxybiphenyls (PCBs) has been tested for their binding activity to soluble uterine estrogen receptor protein. Competitive binding analysis was performed on 0-40% ammonium sulfate-enriched uterine cytosol receptor preparations which improved the binding activity for the PCB compounds by a factor of 10-40, by decreasing the nonspecific binding. The binding activities have been correlated to molecular properties supported by molecular modeling studies which emphasize the importance of conformational restriction. The estrogen receptor bound 4-hydroxy-2',4',6'-trichlorobiphenyl (4H2',4',6'TCB) with the greatest affinity, with the concentration of unlabeled inhibitor yielding half-maximal specific binding relative to estradiol (C50) being approximately 42 compared to estradiol, C50 approximately 1.0. PCB compounds that demonstrated appreciable receptor-binding activity were also active in vivo in stimulating uterine weight increases, whereas weak binders were inactive. The 4H2',4',6'TCB compound represents a high degree of conformational restriction around the interring bond due to the presence of two ortho-chlorine atoms. The other PCBs in this series, which show lower receptor-binding activity, vary in position of chlorine substituents and can assume multiple low energy conformations as a result of less hindrance to rotation around the interring bond.

Animals↗
PubMed1987

Do residue levels of polychlorinated biphenyls (PCBs) in human blood produce mild hypothyroidism?

PCBs are nearly ubiquitous environmental contaminants, occurring in most human adipose tissue and blood samples. It has recently been recognized that PCBs and related compounds share important structural properties with thyroid hormones and can bind thyroid hormone binding proteins. It is reasonable that such specific binding interactions can modulate the distribution of these compounds in the body and alter hormone-protein interactions that are responsible for the maintenance of normal thyroid status. Most of the available evidence indicates that the levels of free thyroid hormones in plasma are a reflection of the maintenance of normal thyroid status in any individual. A theoretical model for the transport of thyroid hormones in blood has been extended to estimate the modulating effects of PCBs on free thyroid hormones. Using conservative assumptions based on experimental data, our calculations indicate that PCB concentrations normally found in humans can effect significant increases in free thyroxine levels in serum by competing with serum thyroid hormone binding proteins. Experimental data are discussed which support the proposal that antagonist binding of PCBs to thyroid hormone binding proteins in serum could produce varying degrees of hypothyroidism. The biological result is compatible with the "equilibrium hypothesis" in which thyroid hormone redistributes between specific and nonspecific binding proteins rather than emphasizing the importance of free hormone as the active moiety.

Animals↗
PubMed1987

Modulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated myelotoxicity by thyroid hormones.

Although binding by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the Ah receptor is a prerequisite for toxicity, the events responsible for subsequent TCDD effects are essentially unknown. Several lines of evidence have indicated that thyroid hormones share common molecular properties with TCDD and can modulate its toxicity. In the present studies we employed suppression of murine bone marrow hematopoiesis by TCDD as an in vitro model to study the relationship between thyroid hormones and TCDD toxicity. Supraphysiological levels of thyroid hormone mimicked TCDD myelotoxicity, in that both were inhibited by a common antagonist, 1-NH2-3,7,8-trichlorodibenzo-p-dioxin. Furthermore, myelotoxicity by both TCDD and thyroid hormone segregated with the Ah locus in congenic mice. These data provide evidence of a relationship between TCDD and thyroid hormones in that hormonal activity may help regulate TCDD toxicity.

Animals↗
PubMed1987

Overexpression and purification of a biologically active rifampicin-resistant beta subunit of Escherichia coli RNA polymerase.

The gene rpoB (rifD 18), which encodes rifampicin-resistant beta subunit of Escherichia coli RNA polymerase, has been placed on an overexpression plasmid under the control of bacteriophage T7 promoter. Induction of the T7 RNA polymerase gene in the host cells resulted in extensive overproduction of the beta polypeptide. Most of the overproduced material was recovered from cell lysates in insoluble form and was solubilized by extraction with 6 M urea. Purified overproduced beta subunit was added, in molar excess, to urea-denatured rifampicin-sensitive RNA polymerase. Upon removal of urea by dialysis, the reconstituted enzyme became rifampicin-resistant, indicating that overproduced beta subunit can be efficiently assembled into functional holoenzyme.

DNA-Directed RNA Polymerases↗