Biomedical subjects

Larry W Robertson

Publications and source records attributed to Larry W Robertson.

40 records · Page 3Linked to original sources

PubMed2002

Glucuronidation of hydroxylated polychlorinated biphenyls (PCBs).

Polychlorinated biphenyls (PCBs) may be metabolized to hydroxylated compounds. While many of these metabolites are further converted to either the glucuronic acid or the sulfate conjugates by phase II enzymes, which facilitates their excretion, some hydroxylated PCBs persist in the body. This may reflect their inability to be conjugated. A possible role of uridine diphosphate glucuronosyl transferase (UGT) in the elimination of hydroxylated metabolites of PCBs was therefore investigated. Glucuronidation studies of PCB metabolites included ones which are eliminated with relative ease and also ones which are reported to be retained in blood. Liver microsomes, prepared from male Wistar rats treated by intraperitoneal injections of phenobarbital for 3 days (400 micromol/kg/day), were used as the source of UGT. Enzyme kinetics (V(max) and K(m)) were determined for each of the metabolites. The efficiency of glucuronidation (V(max)/K(m)) was found to vary from <3 to 116 microL/min/mg and was dependent on the structure of the metabolites. Substitution of chlorine atoms on the nonhydroxylated ring greatly lowered the V(max) of the enzyme, with substitution in the meta and para positions being least favorable for enzyme activity. Steric hindrance around the hydroxyl group by chlorines on adjacent carbon atoms did not play a major role. A weak relationship between the calculated dihedral angle (planarity), pK(a), log D, and enzyme activity was determined (r(2) < 0.5). However, a stronger relationship for the surface area and surface volume of the molecule was observed (r(2) >or= 0.5). This study explains in part why some PCB metabolites persist in the body.

Animals↗

PubMed2002

PCB-induced oxidative stress in endothelial cells: modulation by nutrients.

There is an increasing body of evidence suggesting that exposure to Superfund chemicals may have adverse consequences on many organ systems, as well as carcinogenic and atherogenic effects. This is particularly true for polyhalogenated aromatic hydrocarbons such as the polychlorinated biphenyls (PCBs). The vascular endothelium, which is constantly exposed to blood components including environmental contaminants, is extremely vulnerable to chemical insult as well as necrotic and apoptotic injury. Our recent studies suggest that certain PCBs, especially coplanar PCBs, can compromise normal functions of vascular endothelial cells by activating oxidative stress-sensitive signaling pathways and subsequent proinflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. Our findings suggest that an increase in the level of cellular oxidative stress is a significant event in PCB-mediated endothelial cell dysfunction and that nutrients can modulate PCB-induced oxidative stress and endothelial toxicity. We have demonstrated that the dietary fat linoleic acid, the parent unsaturated fatty acid of the omega-6 family, can increase endothelial dysfunction induced by selected PCBs, probably by contributing to oxidative stress and as the result of the production of toxic metabolites called leukotoxins. The subsequent imbalance in the overall cellular oxidant/antioxidant status can activate oxidative stress- or redoxsensitive transcription factors, which in turn promote gene expression for inflammatory cytokines and adhesion molecules, intensifying the inflammatory response and endothelial cell dysfunction. Our data also suggest that antioxidant nutrients such as vitamin E can protect against endothelial cell damage mediated by PCBs or polyunsaturated dietary fats by interfering with oxidative stress-sensitive and proinflammatory signaling pathways. The concept that nutrition can modify or ameliorate the toxicity of Superfund chemicals is provocative and warrants further study as the implications for human health are significant. The information from such studies could be used to develop dietary recommendations and nutritional interventions for populations at high risk for exposure to PCBs, including communities living near Superfund sites and those exposed via occupation or diet.

Diet↗

PubMed2001

Z' = 4 structure without obvious pseudosymmetry: implications for the formation of solid-state compounds.

Crystals of 4-chloro-2'-biphenylol grown at 263 K and studied at both 293 and 142 K are loosely packed and contain OH.O bonded tetramers composed of four crystallographically independent molecules (Z' = 4). Approximate symmetry relationships between independent molecules are apparent in many, perhaps even most, structures with Z' > 1, but are not obvious in this structure. The inefficient crystal packing, the surprisingly large value of Z' and the absence of pseudosymmetry reflect the difficulty of finding a dense molecular arrangement that also allows for hydrogen-bond formation. Impediments to good packing are the steric congestion around the ortho hydroxyl groups and the difficulty in filling space with significantly twisted biphenyl fragments. The packing arrangement adopted is strongly reminiscent of the structure type found for eight simple 4,4'-biphenyl derivatives, but one of the four independent 4-chloro-2'-biphenylol molecules has an orientation that is significantly different from the orientations of the other three and that does not fit the 4,4'-XPhPhY pattern. It is suggested that molecules that crystallize with Z' > 1 are good candidates for solid-state compound formation.

Biphenyl Compounds↗

PubMedDate not supplied

Comparison of the actions of 4-chlorobiphenyl and its hydroxylated metabolites on estradiol secretion by ovarian follicles in primary cells in culture.

Theca interna and granulosa cells from small, medium and large preovulatory porcine follicles were cultured as a monolayer to compare the effects of 4-chlorobiphenyl (PCB3) and its metabolites on estradiol secretion. Cells were treated with PCB3 or its mono- and di-hydroxylated metabolites 4-OH-PCB3 and 3,4-di-OH-PCB3 at concentrations of 0.06, 0.6, 6 and 60 ng/ml medium for 24 h. Each compound significantly increased estradiol levels detected in the medium of small, medium and large follicle cultures. This effect was evident at even the lowest concentration tested (0.06 ng/ml). A time-series with 6.0 ng/ml PCB3 or metabolites showed estrogenic action at each test interval (24, 48, 72, 96 h) and established a rankorder potency of 3,4-OH-PCB>4-OH-PCB3>or=PCB3. In small and medium follicles treated with PCB3 metabolites the temporal increase led to estradiol accumulations >20,000-fold over control culture media. Large preovulatory follicles had the highest estrogenic action at 72 h of exposure, decreasing somewhat at 96 h. These findings indicate that PCB3 and its hydroxylated metabolites induce a surge in estradiol secretion in ovarian follicle cells. Such a response would in vivo be expected to disrupt reproductive processes, through enhanced aging of the follicle and negative feedback to the hypothalamus, and perhaps increase the risk for ovarian and breast cancer.

Animals↗