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Biomedical subjects

S D Nelson

Publications and source records attributed to S D Nelson.

At least 199 records · Page 11Linked to original sources
PubMed1981

In vitro and in vivo covalent binding of the kidney toxicant and carcinogen tris(2,3-dibromopropyl)-phosphate.

The nephrotoxicant and nephrocarcinogen tris(2,3-dibromopropyl)-phosphate (Tris-BP) is activated to products which bind covalently to microsomal protein by a cytochrome P-450 dependent oxidation reaction. Binding to rat liver microsomes proceeds 15 times faster than with kidney microsomes. The binding in liver microsomes is markedly increased by phenobarbital pretreatment, the apparent Vmax of the reaction is 175 pmol/mg microsomal protein/min with control microsomes and 1053 pmol/mg protein/min with induced microsomes. Binding with kidney microsomes is doubled after pretreatment with polychlorinated biphenyls. 2,3-Dibromopropanol (2,3-DBP), a hydrolysis product of Tris-BP, is also activated to covalently protein-bound products, but at a much slower rate than Tris-BP. Administration of Tris-BP to rats leads to its covalent binding to proteins in liver and kidney, with 5 time higher binding levels in kidney than in liver, correlating with its relative organotoxic potential in single dose experiments. Binding to proteins in the kidney was increased by pretreatment of animals with polychlorinated biphenyls. A covalent interaction of Tris-BP could also be demonstrated to DNA, both when DNA was added to liver microsomal incubations in vitro and to DNA extracted from liver and kidney after administration of Tris-BP in vivo. The binding levels were 4 times higher to kidney DNA than to liver DNA.

Animals↗
PubMed1981

Protein binding of valproic acid in the presence of elevated free fatty acids in patient and normal human serum.

Two recent reports indicate that free fatty acids (FFA) can decrease the binding of valproic acid (VPA) to plasma proteins. Since FFA can increase in several physiological and clinical situations, it becomes necessary to define the relationship between elevated FFA and VPA free fraction. This study was conducted in two phases. In the first phase, serum was obtained from nine patients who were receiving Intralipid. A base-line sample was taken when therapy was absent. A second sample was taken during or immediately after Intralipid therapy. Protein binding VPA (equilibrium dialysis) and FFA levels were determined on each sample. FFA increased in eight patients; the median increase was 80.1%. VPA free fractions increased in six of the eight patients showing an increase in FFA; the median increase in free fraction was 18.7%. Rank correlation between FFA differences and free fraction differences indicated a significant positive linear correlation (r = 0.800). In the second phase, oleic acid was added to normal serum in five different concentrations (500-5,000 microEq/liter) with VPA at 100 microgram/ml. Free fraction of VPA increased continuously from a blank value of 9.6% (+/- 1.4) to 44.1% (+/- 2.5) with increasing concentrations of oleic acid.

Fat Emulsions, Intravenous↗
PubMed1981

Genetic differences in dimethylnitrosamine mutagenicity in vitro associated with mouse hepatic aryl hydrocarbon hydroxylase activity induced by 3-methylcholanthrene.

The effects of 3-methylcholanthrene (MC) pretreatment on metabolism and mutagenic activation of dimethylnitrosamine (DMN) were studied with liver subfractions from two strains of mice differing genetically with respect to aromatic hydrocarbon responsiveness. Both mutagenic activation and DMN N-demethylase activity segregated with aryl hydrocarbon (benzo[a]pyrene) hydroxylase activity as a dominant trait in appropriate crosses between C57BL/6J (Ahb Ahb) and DBA/2J (Ahd Ahd) mice. DMN metabolism and mutagenicity were increased by MC-pretreatment in responsive Ahb Ahb and Ahb Ahd mice, but not in non-responsive Ahd Ahd mice. This indicates the involvement of the Ah locus in the genetic regulation of these activities in mice. Deuteration of DMN reduced mutagenicity and DMN N-demethylase activity by approximately 90 and 50 percent, respectively.

Animals↗
PubMed1981

Catechol estrogen formation in placental and fetal tissues of humans, macaques, rats and rabbits.

Placental and fetal tissues obtained from humans, monkeys, rats and rabbits contained monooxygenases capable of catalyzing the formation of catechol estrogens. Treatments of pregnant rats with phenobarbital, Aroclor 1254, or 3-methylcholanthrene each increased measured rates of catechol estrogen formation in placentas, fetal brains and fetal livers, while other rat tissues exhibited either increased or decreased activity. Treatment of pregnant rabbits with Arocolor 1254 produced an increase in catechol estrogen formation in all fetal tissues studied and in the maternal liver and kidney. Catechol estrogen formation in placental microsomes of macaque monkeys (Macaca arctoides) was generally less than that observed in human placental microsomes. Human placentas obtained from smokers exhibited enhanced catechol estrogen formation and this activity appeared to be highly correlated with placental aryl hydrocarbon hydroxylase activity. The data suggested [a]pyrene in a similar fashion in placental tissues and that the enzyme systems involved may be under similar regulatory control.

Animals↗
PubMed1980

Advantages of low dose steroid from the day after renal transplantation.

We have used a low dose of steroid (20 mg of prednisolone), commencing the day after transplantation, for 151 consecutive renal transplants in 141 patients. Five patients received grafts from living related donors, 146 received cadaver grafts. All patients received azathioprine for routine immunosuppression and the first 47 received a single dose of actinomycin C i.v. for treatment of rejection. No other immunosuppressive drugs were used. This treatment provided satisfactory immunosuppression as 109 of 151 grafts continue to function for periods of 3 months to 10 years and, of 42 grafts lost, only 17 failed from rejection. The cumulative survival of first cadaver grafts at 1 and 2 years in recipients of all ages (7 to 55 years) was 77.9 and 76.0%, respectively; in recipients 15 to 34 years old, 90.9 and 86.1%, respectively. Twenty-three patients died, no patient died from infection during the admission for transplantation, and infection played a part in the deaths of only four patients. The incidence of other complications was low; seven patients developed gastrointestinal complications, one died, four patients developed diabetes, all survived; only one patient developed avascular necrosis of bone.

Administration, Oral↗
PubMed1980

Isoniazid hepatoxicity: the relationship between covalent binding and metabolism in vivo.

The relationship between the hepatotoxicity and metabolism of isoniazid and its metabolites, acetylisoniazid and acetylhydrazine, has been investigated. Toxic doses of acetylisoniazid and acetylhydrazine, radiolabeled in the acetyl group, were found to bind covalently to liver protein in vivo. This binding was mediated by the microsomal enzyme system as indicated by the effects of pretreatments altering the activity of these enzymes. Metabolic studies revealed that the pretreatments increased the metabolism of the acetylhydrazine moiety of acetyl-labeled acetylisoniazid and of acetylhydrazine itself by the microsomal enzyme system. Pretreatment with the acyl amidase inhibitor, bis-p-nitrophenyl phosphate, inhibited the hydrolysis of acetylisoniazid to isonicotinic acid plus acetylhydrazine and concomitantly decreased the covalent binding of acetyl-labeled acetylisoniazid. The changes in the metabolism of isoniazid, acetylisoniazid and acetylhydrazine effected by various pretreatments paralleled changes in the severity of the hepatic necrosis caused by the compounds. These results strongly suggest that acetylhydrazine is the metabolite responsible for the hepatic necrosis caused by isoniazid and that mirosomal metabolism of acetylhydrazine in vivo leads to the production of a reactive acylating species capable of reacting covalently with tissue macromolecules.

Acetylation↗